title: Phase 1 and pharmacokinetic study of everolimus, a mammalian target of rapamycin inhibitor, in combination with docetaxel for recurrent/refractory nonsmall cell lung cancer.
abstract: BACKGROUND
  Everolimus is a novel inhibitor of the mammalian target of rapamycin pathway, which is aberrantly activated in nonsmall cell lung cancer (NSCLC). The authors conducted a phase 1 and pharmacokinetic study of everolimus and docetaxel for recurrent NSCLC.
  
  
  METHODS
  Patients with advanced stage NSCLC and progression after prior platinum-based chemotherapy were eligible. Sequential cohorts were treated with escalating doses of docetaxel (Day 1) and everolimus (orally daily, Days 1-19) every 3 weeks. Pharmacokinetic sampling of everolimus and docetaxel was done in Cycle 1. The primary endpoint was determination of the recommended phase 2 doses of the combination.
  
  
  RESULTS
  Twenty-four patients were enrolled (median age, 62 years; women, 11; number of prior regimens, 1 [n=13], 2 [n=6], >or=3 [n=5]; Eastern Cooperative Oncology Group performance status, 0 [n=6], 1 [n=17]). The dose-limiting toxicities (DLTs) were fever with grade 3/4 neutropenia, grade 3 fatigue, and grade 3 mucositis. None of the 7 patients treated at the recommended phase 2 dose (docetaxel 60 mg/m2 and everolimus 5 mg daily) experienced DLT. Everolimus area under the concentration time curve (AUC) was not different with 60 or 75 mg/m2 docetaxel. Mean+/-standard deviation AUC-based accumulation factors for everolimus on Days 8 and 15 were 1.16+/-0.37 and 1.42+/-0.42, respectively. Docetaxel Day 1 half-life was 9.4+/-3.4 hours. Among 21 patients evaluable, 1 had a partial response, and 10 had disease stabilization.
  
  
  CONCLUSIONS
  The recommended phase 2 doses of docetaxel and everolimus for combination therapy are 60 mg/m2 and 5 mg orally daily, respectively. Promising anticancer activity has been noted.
authors.affiliation: Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia 30322, USA. ssramal@emory.edu
authors.forename: Suresh S
authors.initials: SS
authors.lastname: Ramalingam
authors.forename: R Donald
authors.initials: RD
authors.lastname: Harvey
authors.forename: Nabil
authors.initials: N
authors.lastname: Saba
authors.forename: Taofeek K
authors.initials: TK
authors.lastname: Owonikoko
authors.forename: John
authors.initials: J
authors.lastname: Kauh
authors.forename: Dong M
authors.initials: DM
authors.lastname: Shin
authors.forename: Shi-Yong
authors.initials: SY
authors.lastname: Sun
authors.forename: Sandra
authors.initials: S
authors.lastname: Strychor
authors.forename: Mourad
authors.initials: M
authors.lastname: Tighiouart
authors.forename: Merrill J
authors.initials: MJ
authors.lastname: Egorin
authors.forename: Haian
authors.initials: H
authors.lastname: Fu
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D000077143:Docetaxel; D004334:Drug Administration Schedule; D000068338:Everolimus; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D043823:Taxoids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D043823:Taxoids; D000077143:Docetaxel; D000068338:Everolimus; D020123:Sirolimus