title: Phase I study of the farnesyltransferase inhibitor lonafarnib with paclitaxel in solid tumors.
abstract: OBJECTIVE
  To establish the maximum tolerated dose of lonafarnib, a novel farnesyltransferase inhibitor, in combination with paclitaxel in patients with solid tumors and to characterize the safety, tolerability, dose-limiting toxicity, and pharmacokinetics of this combination regimen.
  
  
  METHODS
  In a Phase I trial, lonafarnib was administered p.o., twice daily (b.i.d.) on continuously scheduled doses of 100 mg, 125 mg, and 150 mg in combination with i.v. paclitaxel at doses of 135 mg/m(2) or 175 mg/m(2) administered over 3 h on day 8 of every 21-day cycle. Plasma paclitaxel and lonafarnib concentrations were collected at selected time points from each patient.
  
  
  RESULTS
  Twenty-four patients were enrolled; 21 patients were evaluable. The principal grade 3/4 toxicity was diarrhea (5 of 21 patients), which was most likely due to lonafarnib. dose-limiting toxicities included grade 3 hyperbilirubinemia at dose level 3 (100 mg b.i.d. lonafarnib and 175 mg/m(2) paclitaxel); grade 4 diarrhea and grade 3 peripheral neuropathy at dose level 3A (125 mg b.i.d. lonafarnib and 175 mg/m(2) paclitaxel); and grade 4 neutropenia with fever and grade 4 diarrhea at level 4 (150 mg b.i.d. lonafarnib and 175 mg/m(2) paclitaxel). The maximum tolerated dose established by the continual reassessment method was lonafarnib 100 mg b.i.d. and paclitaxel 175 mg/m(2). Paclitaxel appeared to have no effect on the pharmacokinetics of lonafarnib. The median duration of therapy was eight cycles, including seven cycles with paclitaxel. Six of 15 previously treated patients had a durable partial response, including 3 patients who had previous taxane therapy. Notably, two of five patients with taxane-resistant metastatic non-small cell lung cancer had partial responses.
  
  
  CONCLUSIONS
  When combined with paclitaxel, the recommended dose of lonafarnib for Phase II trials is 100 mg p.o. twice daily with 175 mg/m(2) of paclitaxel i.v. every 3 weeks. Additional studies of lonafarnib in combination regimens appear warranted, particularly in patients with non-small cell lung cancer.
authors.affiliation: Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA. fkhuri@emory.edu
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.forename: Bonnie S
authors.initials: BS
authors.lastname: Glisson
authors.forename: Edward S
authors.initials: ES
authors.lastname: Kim
authors.forename: Paul
authors.initials: P
authors.lastname: Statkevich
authors.forename: Peter F
authors.initials: PF
authors.lastname: Thall
authors.forename: Michael L
authors.initials: ML
authors.lastname: Meyers
authors.forename: Roy S
authors.initials: RS
authors.lastname: Herbst
authors.forename: Reginald F
authors.initials: RF
authors.lastname: Munden
authors.forename: Craig
authors.initials: C
authors.lastname: Tendler
authors.forename: Yali
authors.initials: Y
authors.lastname: Zhu
authors.forename: Sandra
authors.initials: S
authors.lastname: Bangert
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Thompson
authors.forename: Charles
authors.initials: C
authors.lastname: Lu
authors.forename: Xue-Mei
authors.initials: XM
authors.lastname: Wang
authors.forename: Dong M
authors.initials: DM
authors.lastname: Shin
authors.forename: Merrill S
authors.initials: MS
authors.lastname: Kies
authors.forename: Vali
authors.initials: V
authors.lastname: Papadimitrakopoulou
authors.forename: Frank V
authors.initials: FV
authors.lastname: Fossella
authors.forename: Paul
authors.initials: P
authors.lastname: Kirschmeier
authors.forename: W Robert
authors.initials: WR
authors.lastname: Bishop
authors.forename: Waun Ki
authors.initials: WK
authors.lastname: Hong
mesh_terms: D000328:Adult; D000368:Aged; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D000740:Anemia / Q000139:chemically induced; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D051231:Farnesyltranstransferase; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006323:Heart Arrest / Q000139:chemically induced; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009503:Neutropenia / Q000139:chemically induced; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome; D003986:Dibenzocycloheptenes
chemical_list: D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D017239:Paclitaxel; D010880:Piperidines; D011725:Pyridines; C115354:lonafarnib; D003986:Dibenzocycloheptenes