title: Phase I study of weekly paclitaxel in combination with pazopanib and lapatinib in advanced solid malignancies.
abstract: BACKGROUND
  We assessed the maximum tolerated regimen (MTR) and dose-limiting toxicities of pazopanib and lapatinib in combination with weekly paclitaxel, and the effect of pazopanib and lapatinib on paclitaxel pharmacokinetics.
  
  
  METHODS
  Patients received intravenous paclitaxel on days 1, 8, and 15 of a 28-day cycle concurrently with daily pazopanib and lapatinib. Dose levels of paclitaxel (mg m(-2))/pazopanib(mg)/lapatinib(mg) were 50/400/1000, 50/800/1000, 80/800/1000, and 80/400/1000. At the MTR, additional patients were enrolled to further evaluate tolerability, and the potential effects of pazopanib and lapatinib, inhibitors of cytochrome P450 (CYP)3A4, on the pharmacokinetics of paclitaxel, a CYP2C8 and CYP3A4 substrate.
  
  
  RESULTS
  Twenty-six patients were enrolled. Dose-limiting toxicities at the MTR (80/400/1000) included grade 4 thrombosis and grade 3 aspartate aminotransferase elevation. Other toxicities included diarrhoea, neutropenia, fatigue, and liver enzyme elevations. Coadministration of pazopanib 400 mg and lapatinib 1000 mg increased paclitaxel maximum plasma concentration (38%) and area under the curve (37%) relative to paclitaxel alone. One patient with a salivary gland tumour had a partial response; three patients had stable disease (⩾6 months).
  
  
  CONCLUSIONS
  Pazopanib 400 mg per day and lapatinib 1000 mg per day can be combined with paclitaxel 80 mg m(-2) in 28-day cycles. Coadministration of pazopanib and lapatinib, weak inhibitors of CYP2C8 and CYP3A4, had an inhibitory effect on paclitaxel clearance.
authors.affiliation: Rutgers Cancer Institute of New Jersey,195 Little Albany Street, New Brunswick, NJ 08903, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Tan
authors.affiliation: University Hospitals Case Medical Center, Case Western Reserve University, 11100 Euclid Ave, Cleveland, OH 44106, USA.
authors.forename: A
authors.initials: A
authors.lastname: Dowlati
authors.affiliation: Rutgers Cancer Institute of New Jersey,195 Little Albany Street, New Brunswick, NJ 08903, USA.
authors.forename: M N
authors.initials: MN
authors.lastname: Stein
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, PLLC, 3322 West End Avenue, Nashville, TN 37203, USA.
authors.forename: S F
authors.initials: SF
authors.lastname: Jones
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, PLLC, 3322 West End Avenue, Nashville, TN 37203, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Infante
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, PLLC, 3322 West End Avenue, Nashville, TN 37203, USA.
authors.forename: J
authors.initials: J
authors.lastname: Bendell
authors.affiliation: Rutgers Cancer Institute of New Jersey,195 Little Albany Street, New Brunswick, NJ 08903, USA.
authors.forename: M P
authors.initials: MP
authors.lastname: Kane
authors.affiliation: Rutgers Cancer Institute of New Jersey,195 Little Albany Street, New Brunswick, NJ 08903, USA.
authors.forename: K T
authors.initials: KT
authors.lastname: Levinson
authors.affiliation: GlaxoSmithKline, Five Moore Drive, PO Box 13398, Research Triangle Park, NC 27709, USA.
authors.forename: A B
authors.initials: AB
authors.lastname: Suttle
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, PLLC, 3322 West End Avenue, Nashville, TN 37203, USA.
authors.forename: H A
authors.initials: HA
authors.lastname: Burris
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D001661:Biliary Tract Neoplasms / Q000188:drug therapy*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007191:Indazoles; D000077341:Lapatinib; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage; D012468:Salivary Gland Neoplasms / Q000188:drug therapy*; D013449:Sulfonamides / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D007191:Indazoles; D011743:Pyrimidines; D011799:Quinazolines; D013449:Sulfonamides; D000077341:Lapatinib; C516667:pazopanib; D017239:Paclitaxel