title: A phase I dose escalation and pharmacodynamic study of SU5416 (semaxanib) combined with weekly cisplatin and irinotecan in patients with advanced solid tumors.
abstract: BACKGROUND
  This phase I study evaluated the safety of SU5416, a potent and selective inhibitor of the vascular endothelial growth factor (VEGF) receptor tyrosine kinase Flk-1, in combination with weekly cisplatin and irinotecan in patients with advanced solid tumors.
  
  
  METHODS
  The patients received cisplatin 30 mg/m² and irinotecan 50 mg/m² weekly from week 1 to week 4, with SU5416 at either 65 mg/m² (dose level (DL)1) or 85 mg/m² (DL2) twice weekly for 6 weeks (1 cycle). Serial ¹⁸fluorodeoxyglucose-positron emission tomography (¹⁸FDG-PET) and ¹⁵O-H₂O-PET scans were obtained.
  
  
  RESULTS
  13 patients were treated (7 on DL1, 6 on DL2); 7 patients completed at least 1 cycle of treatment. 3 patients experienced dose-limiting toxicity (DLT) at DL2 (grade 3 neutropenia and grade 3 thrombocytopenia causing treatment delay, grade 3 nausea/vomiting). No objective responses were observed at DL1, which was determined to be the maximum tolerated dose (MTD). 1 partial response (PR) was observed at DL2. ¹⁸FDG-PET responses were documented but did not predict response according to the Response Evaluation Criteria in Solid Tumors (RECIST).
  
  
  CONCLUSIONS
  SU5416 at 65 mg/m² twice weekly combined with cisplatin and irinotecan weekly for 4 of 6 weeks is well tolerated but without evidence of clinical activity. ¹⁸FDG-PET may be a useful pharmacodynamic marker of SU5416 bioactivity but requires additional development.
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Medical Center, The Ohio State University Comprehensive Cancer Center, The James Cancer Hospital and Solove Research Institute, Columbus, OH, USA.
authors.forename: Ludmila K
authors.initials: LK
authors.lastname: Martin
authors.forename: Tanios
authors.initials: T
authors.lastname: Bekaii-Saab
authors.forename: Derek
authors.initials: D
authors.lastname: Serna
authors.forename: Paul
authors.initials: P
authors.lastname: Monk
authors.forename: Steven K
authors.initials: SK
authors.lastname: Clinton
authors.forename: Michael R
authors.initials: MR
authors.lastname: Grever
authors.forename: Eric H
authors.initials: EH
authors.lastname: Kraut
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D064146:Chemotherapy-Induced Febrile Neutropenia / Q000175:diagnosis / Q000209:etiology*; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced* / Q000175:diagnosis; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism*; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D013921:Thrombocytopenia / Q000175:diagnosis / Q000209:etiology*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; C116890:Semaxinib; D000077146:Irinotecan; D002945:Cisplatin; D002166:Camptothecin