title: Phase Ib trial of the oral angiogenesis inhibitor pazopanib administered concurrently with erlotinib.
abstract: BACKGROUND
  As angiogenic pathways have become important targets for inhibition of tumor growth, we examined the concept of dual pathway blockade by small-molecule tyrosine kinase inhibitors targeting vascular endothelial and epidermal growth factor receptors.
  
  
  METHODS
  Escalating doses of pazopanib (400-800 mg once daily [QD]) plus erlotinib (100-150 mg QD) doses were evaluated in cohorts of 3-6 adults with advanced solid tumors. Twelve additional patients were enrolled in an expansion cohort to confirm the maximum tolerated dose (MTD).
  
  
  RESULTS
  The MTD, defined during assessment of 20 patients, was pazopanib 600 mg plus erlotinib 150 mg. Two dose-limiting toxicities, rash and elevated liver enzymes, occurred at pazopanib 800 mg and erlotinib 150 mg. Overall, 30 % and 27 % of patients required dose interruption of pazopanib or erlotinib, respectively; 15 % of patients required a dose reduction of erlotinib to manage toxicities. The most common adverse events in patients treated with any dose regimen of pazopanib plus erlotinib (N = 33) were diarrhea, rash, nausea, and decreased appetite. The adverse-event profile of the combination did not appear to differ from that of each compound administered alone. Coadministration of pazopanib 600 mg QD and erlotinib 150 mg QD did not consistently affect the pharmacokinetics of either compound relative to that observed for either compound administered alone. Of 26 patients evaluated for efficacy, 3 (12 %; all non-small-cell lung cancer) had partial response and 10 (38 %) had stable disease.
  
  
  CONCLUSIONS
  Concomitant administration of pazopanib 600 mg and erlotinib 150 mg is feasible, with a manageable toxicity profile. These results support further clinical development of the pazopanib-erlotinib combination.
authors.affiliation: Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA.
authors.forename: Grace K
authors.initials: GK
authors.lastname: Dy
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.forename: S Gail
authors.initials: SG
authors.lastname: Eckhardt
authors.forename: Silvia
authors.initials: S
authors.lastname: Novello
authors.forename: Wen Wee
authors.initials: WW
authors.lastname: Ma
authors.forename: Suzanne F
authors.initials: SF
authors.lastname: Jones
authors.forename: Anne
authors.initials: A
authors.lastname: Huff
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wang
authors.forename: A Benjamin
authors.initials: AB
authors.lastname: Suttle
authors.forename: Lone H
authors.initials: LH
authors.lastname: Ottesen
authors.forename: Alex A
authors.initials: AA
authors.lastname: Adjei
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003710:Demography; D004305:Dose-Response Relationship, Drug; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D007191:Indazoles; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011743:Pyrimidines / Q000008:administration & dosage* / Q000627:therapeutic use*; D011799:Quinazolines / Q000008:administration & dosage* / Q000627:therapeutic use*; D013449:Sulfonamides / Q000008:administration & dosage* / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D007191:Indazoles; D011743:Pyrimidines; D011799:Quinazolines; D013449:Sulfonamides; C516667:pazopanib; D000069347:Erlotinib Hydrochloride