title: A phase I dose escalation and pharmacokinetic study of vatalanib (PTK787/ZK 222584) in combination with paclitaxel in patients with advanced solid tumors.
abstract: OBJECTIVE
  To define the maximum-tolerated dose (MTD) for weekly paclitaxel administered in combination with daily vatalanib (PTK787/ZK 222584, PTK/ZK) and assess for a drug-drug interaction.
  
  
  METHODS
  Patients were treated with escalating doses of weekly paclitaxel (75-85 mg/m(2)), and daily PTK/ZK (250-1,000 mg). During the first cycle only, paclitaxel was given on days 1 and 15, and PTK/ZK on days 3-28. Pharmacokinetic studies were conducted on cycle 1 days 1 and 15 for paclitaxel, and on cycle 1 day 15 for PTK/ZK. Therapy was given until disease progression.
  
  
  RESULTS
  Twenty-seven patients were accrued to four dose levels. Two of five patients treated with paclitaxel 85 mg/m(2) and PTK/ZK 1,000 mg had Grade 3 transaminase elevation as dose-limiting toxicity. Paired PK analyses demonstrated a significant increase in paclitaxel clearance on day 15 (p = 0.006). Activity included one partial response and 11 patients with stable disease > or =4 months, including patients previously treated with paclitaxel.
  
  
  CONCLUSIONS
  The MTD for weekly paclitaxel plus daily PTK/ZK is 75 mg/m(2) and 750 mg. PK analysis revealed a significant drug-drug interaction, with an increase in paclitaxel clearance. This combination was well tolerated with evidence of anti-cancer activity and provides guidance for phase 2 planning.
authors.affiliation: Department of Medicine, Indiana University Simon Cancer Center, Indianapolis, IN, USA.
authors.forename: E Gabriela
authors.initials: EG
authors.lastname: Chiorean
authors.forename: Srikar
authors.initials: S
authors.lastname: Malireddy
authors.forename: Anne E
authors.initials: AE
authors.lastname: Younger
authors.forename: David R
authors.initials: DR
authors.lastname: Jones
authors.forename: Mary-Jane
authors.initials: MJ
authors.lastname: Waddell
authors.forename: Melissa I
authors.initials: MI
authors.lastname: Sloop
authors.forename: Menggang
authors.initials: M
authors.lastname: Yu
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Hall
authors.forename: Bryan
authors.initials: B
authors.lastname: Schneider
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Sweeney
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage; D010793:Phthalazines / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D000637:Transaminases / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D010793:Phthalazines; D011725:Pyridines; C404768:vatalanib; D000637:Transaminases; D017239:Paclitaxel