title: Phase I study and preclinical efficacy evaluation of the mTOR inhibitor sirolimus plus gemcitabine in patients with advanced solid tumours.
abstract: 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 5 mg 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 5 mg 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 5 mg 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.
authors.affiliation: The Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK.
authors.forename: J
authors.initials: J
authors.lastname: Martin-Liberal
authors.affiliation: Institut Català d'Oncologia L'Hospitalet, Genitourinary Tumors, Sarcoma and Melanoma Unit, Avda Gran Via 199, L'Hospitalet, 08908 Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Gil-Martín
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskjöldsv 20, 751 85 Uppsala, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Sáinz-Jaspeado
authors.affiliation: Institut Català d'Oncologia L'Hospitalet, Laboratori de Farmacocinètica, Avda Gran Via 199, L'Hospitalet, 08908 Barcelona, Spain.
authors.forename: N
authors.initials: N
authors.lastname: Gonzalo
authors.affiliation: Hospital de Bellvitge, Àrea de Bioquímica i Biologia Molecular, Feixa Llarga s/n, L'Hospitalet, 08907 Barcelona, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Rigo
authors.affiliation: Universitat de Barcelona, Facultat de Farmàcia, Avda de Joan XXIII 31, 08028 Barcelona, Spain.
authors.forename: H
authors.initials: H
authors.lastname: Colom
authors.affiliation: Institut Català d'Oncologia L'Hospitalet, Laboratori de Farmacocinètica, Avda Gran Via 199, L'Hospitalet, 08908 Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Muñoz
authors.affiliation: Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Laboratori d'Oncología Molecular, Sarcoma Research Group, Avda Gran Via 199, L'Hospitalet, 08908 Barcelona, Spain.
authors.forename: O M
authors.initials: OM
authors.lastname: Tirado
authors.affiliation: Institut Català d'Oncologia L'Hospitalet, Genitourinary Tumors, Sarcoma and Melanoma Unit, Avda Gran Via 199, L'Hospitalet, 08908 Barcelona, Spain.
authors.forename: X
authors.initials: X
authors.lastname: García del Muro
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D020123:Sirolimus / Q000008:administration & dosage; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus; D000093542:Gemcitabine