title: Everolimus in combination with pemetrexed in patients with advanced non-small cell lung cancer previously treated with chemotherapy: a phase I study using a novel, adaptive Bayesian dose-escalation model.
abstract: BACKGROUND
  Pemetrexed is an established second-line therapy for non-small cell lung cancer (NSCLC). Everolimus has previously been shown to have some clinical activity when used as a single agent in NSCLC. The aim of this phase I study was to evaluate the safety and feasibility of combining pemetrexed with everolimus in patients with NSCLC who had disease progression after one previous treatment.
  
  
  METHODS
  Patients with stage IIIb/IV NSCLC and one previous chemotherapy regimen were enrolled. A Bayesian dose-escalation model was used to determine the feasible doses of daily or weekly everolimus combined with pemetrexed (500 mg/m q3w). The primary end point was rate of cycle 1 dose-limiting toxicities (DLTs). Secondary end points included safety, relative dose intensity of pemetrexed, pharmacokinetics, and tumor response.
  
  
  RESULTS
  Twenty-four patients received daily everolimus (2.5, 5, 7.5, or 10 mg) and 19 received weekly everolimus (30 or 50 mg) with pemetrexed. Cycle 1 DLTs in the daily regimen included febrile neutropenia, neutropenia, rash/pruritus, and thrombocytopenia; in the weekly regimen, DLTs included neutropenia and stomatitis. The most frequent grade 3/4 adverse events were neutropenia, dyspnea, and thrombocytopenia. Three partial responses were observed with everolimus 5 mg/d and two with 50 mg/wk. Pharmacokinetics did not suggest an influence of everolimus on pemetrexed parameters; pemetrexed resulted in a minor decrease in everolimus exposure with both daily and weekly regimens.
  
  
  CONCLUSIONS
  Everolimus 5 mg/d or 50 mg/wk with the standard regimen of pemetrexed are feasible dosages in patients with stage IIIb/IV NSCLC.
authors: University Hospital Gasthuisberg, Leuven, Belgium. johan.vansteenkiste@uzleuven.be
authors: Johan
authors: J
authors: Vansteenkiste
authors: Benjamin
authors: B
authors: Solomon
authors: Michael
authors: M
authors: Boyer
authors: Jürgen
authors: J
authors: Wolf
authors: Neil
authors: N
authors: Miller
authors: Lilla
authors: L
authors: Di Scala
authors: Ilona
authors: I
authors: Pylvaenaeinen
authors: Katarina
authors: K
authors: Petrovic
authors: Sasa
authors: S
authors: Dimitrijevic
authors: Beatrijs
authors: B
authors: Anrys
authors: Eckart
authors: E
authors: Laack
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects* / Q000627:therapeutic use; D001499:Bayes Theorem; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D003875:Drug Eruptions / Q000209:etiology; D004417:Dyspnea / Q000139:chemically induced; D000068338:Everolimus; D005260:Female; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D000068437:Pemetrexed; D011537:Pruritus / Q000139:chemically induced; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D013280:Stomatitis / Q000139:chemically induced; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome
chemical_list: D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; D000068338:Everolimus; D020123:Sirolimus