title: Phase I study of pazopanib in combination with weekly paclitaxel in patients with advanced solid tumors.
abstract: OBJECTIVE
  To evaluate the maximum tolerated regimen (MTR), dose-limiting toxicities, and pharmacokinetics of pazopanib, an oral small-molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit, in combination with paclitaxel.
  
  
  METHODS
  Pazopanib was given daily with weekly paclitaxel on days 1, 8, and 15 every 28 days. Dose levels of pazopanib (mg/day)/paclitaxel (mg/m(2)) were 400/15, 800/15, 800/50, and 800/80. An expanded cohort was enrolled at the MTR. Plasma samples were collected to evaluate the effect of pazopanib, an inhibitor of cytochrome P450 (CYP)3A4, on the pharmacokinetics of paclitaxel, a CYP3A4 and CYP2C8 substrate.
  
  
  RESULTS
  Of 26 enrolled patients, 17 were treated at the MTR of 800 mg pazopanib and 80 mg/m(2) paclitaxel. Dose-limiting toxicities included a grade 3 abscess and grade 2 hyperbilirubinemia. Other toxicities included elevated liver transaminases and diarrhea. Six patients (23%) had partial responses and 15 patients (58%) had stable disease. Administration of 800 mg pazopanib resulted in a 14% lower paclitaxel clearance and a 31% higher paclitaxel maximal concentration than with administration of paclitaxel alone at 15, 50, and 80 mg/m(2). At the MTR, coadministration of 800 mg pazopanib and 80 mg/m(2) paclitaxel resulted in a 26% higher geometric mean paclitaxel area under the curve.
  
  
  CONCLUSIONS
  Pazopanib, at a dose of 800 mg daily, can be safely combined with a therapeutic dose of paclitaxel at 80 mg/m(2) when administered on days 1, 8, and 15, every 28 days. The observed greater plasma concentrations of paclitaxel given concurrently with pazopanib suggest that pazopanib is a weak inhibitor of CYP3A4 and CYP2C8.
authors.affiliation: The Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA. tanan@umdnj.edu
authors.forename: Antoinette R
authors.initials: AR
authors.lastname: Tan
authors.forename: Afshin
authors.initials: A
authors.lastname: Dowlati
authors.forename: Suzanne F
authors.initials: SF
authors.lastname: Jones
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.forename: Jennifer
authors.initials: J
authors.lastname: Nishioka
authors.forename: Lei
authors.initials: L
authors.lastname: Fang
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Hodge
authors.forename: Shelby D
authors.initials: SD
authors.lastname: Gainer
authors.forename: Thangam
authors.initials: T
authors.lastname: Arumugham
authors.forename: A Benjamin
authors.initials: AB
authors.lastname: Suttle
authors.forename: Mohammed M
authors.initials: MM
authors.lastname: Dar
authors.forename: Joanne J
authors.initials: JJ
authors.lastname: Lager
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007191:Indazoles; D008207:Lymphatic Metastasis; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D013449:Sulfonamides / Q000008:administration & dosage; D015996:Survival Rate; D014018:Tissue Distribution; D016896:Treatment Outcome
chemical_list: D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib; D017239:Paclitaxel