title: Safety and pharmacokinetics of paclitaxel and the oral mTOR inhibitor everolimus in advanced solid tumours.
abstract: Everolimus displays antiproliferative effects on cancer cells, yields antiangiogenic activity in established tumours, and shows synergistic activity with paclitaxel in preclinical models. This study assessed the safety and the pharmacokinetic interactions of everolimus and paclitaxel in patients with advanced malignancies. Everolimus was dose escalated from 15 to 30 mg and administered with paclitaxel 80 mg m(-2) on days 1, 8, and 15 every 28 days. Safety was assessed weekly, and dose-limiting toxicity (DLT) was evaluated in cycle 1. A total of 16 patients (median age 54.5 years, range 33-69) were entered; 11 had prior taxane therapy for breast (n=5), ovarian (n=3), and vaginal cancer (n=1) or angiosarcoma (n=2). Grade 3 neutropenia in six patients met the criteria for DLT in two patients receiving everolimus 30 mg weekly. Other drug-related grade 3 toxicities were leucopenia, anaemia, thrombocytopenia, stomatitis, asthenia, and increased liver enzymes. Tumour stabilisation reported in 11 patients exceeded 6 months in 2 patients with breast cancer. Everolimus showed an acceptable safety profile at the dose of 30 mg when combined with weekly paclitaxel 80 mg m(-2), warranting further clinical investigation.
authors.affiliation: Department of Medical Oncology, Centre René Gauducheau, Nantes, France.
authors.forename: M
authors.initials: M
authors.lastname: Campone
authors.forename: V
authors.initials: V
authors.lastname: Levy
authors.forename: E
authors.initials: E
authors.lastname: Bourbouloux
authors.forename: D
authors.initials: D
authors.lastname: Berton Rigaud
authors.forename: D
authors.initials: D
authors.lastname: Bootle
authors.forename: C
authors.initials: C
authors.lastname: Dutreix
authors.forename: U
authors.initials: U
authors.lastname: Zoellner
authors.forename: N
authors.initials: N
authors.lastname: Shand
authors.forename: F
authors.initials: F
authors.lastname: Calvo
authors.forename: E
authors.initials: E
authors.lastname: Raymond
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D000068338:Everolimus; D005260:Female; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D011379:Prognosis; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D015996:Survival Rate; D058570:TOR Serine-Threonine Kinases; D014018:Tissue Distribution; D016896:Treatment Outcome
chemical_list: D000068338:Everolimus; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D017239:Paclitaxel; D020123:Sirolimus