title: Phase Ib trial of the oral angiogenesis inhibitor pazopanib administered concurrently with pemetrexed in patients with advanced solid tumors.
abstract: BACKGROUND
  We sought to define the maximum tolerated dose (MTD) and evaluate the safety, pharmacokinetics, and preliminary clinical activity of pazopanib plus pemetrexed in patients with solid tumors.
  
  
  METHODS
  This dose-escalation study used a standard 3 + 3 design to evaluate once daily pazopanib (400-800 mg) plus pemetrexed (400-500 mg/m(2) on Day 1 of each 21-day cycle). Eight additional patients were enrolled into an expansion cohort.
  
  
  RESULTS
  Twenty-five patients were enrolled. Pazopanib 800 mg plus pemetrexed 500 mg/m(2) was the MTD. The most common adverse events at all dose levels included fatigue, neutropenia, diarrhea, and thrombocytopenia. The frequencies of non-hematologic adverse events were consistent with those of the individual agents. The rates of all-grade and Grade 4 hematologic toxicities (reversible neutropenia with median duration of 4 days) were higher with the combination regimen than with either monotherapy. Exploratory analyses revealed no association between the plasma levels of 3 biomarkers of vitamin B12 metabolism (cystathionine, homocysteine, and methylmalonic acid) and the risk of Grade 4 neutropenia and Grade 3 febrile neutropenia. Of 20 patients evaluated for efficacy, 2 (10 %) had a partial response. Pazopanib did not affect pemetrexed clearance, but increased pemetrexed maximal concentration by 22 %. In exploratory pharmacogenetic analyses, allelic variants of the VEGFA gene demonstrated weak correlation with development of severe neutropenia.
  
  
  CONCLUSIONS
  Concomitant administration of pazopanib 800 mg once daily plus pemetrexed 500 mg/m(2) once every 21 days is feasible, albeit associated with a high frequency of brief, reversible neutropenia. Preliminary activity was observed in non-small-cell lung cancer.
authors.affiliation: Sarah Cannon Research Institute, 250 25th Avenue North, Suite 200, Nashville, TN 37203, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.forename: Silvia
authors.initials: S
authors.lastname: Novello
authors.forename: Wen Wee
authors.initials: WW
authors.lastname: Ma
authors.forename: Grace K
authors.initials: GK
authors.lastname: Dy
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Bendell
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: Robert
authors.initials: R
authors.lastname: Allen
authors.forename: Chun-Fang
authors.initials: CF
authors.lastname: Xu
authors.forename: Lone H
authors.initials: LH
authors.lastname: Ottesen
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
authors.forename: Alex A
authors.initials: AA
authors.lastname: Adjei
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000970:Antineoplastic Agents / 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*; D014408:Biomarkers, Tumor / Q000378:metabolism; D003710:Demography; D004305:Dose-Response Relationship, Drug; D005260:Female; D005971:Glutamates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006147:Guanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D007191:Indazoles; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D000068437:Pemetrexed; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D005971:Glutamates; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; D000068437:Pemetrexed; D006147:Guanine; C516667:pazopanib