title: Phase I/pilot study of SU5416 (semaxinib) in combination with irinotecan/bolus 5-FU/LV (IFL) in patients with metastatic colorectal cancer.
abstract: OBJECTIVE
  Determine the toxicity, tolerability, and pharmacokinetics of SU5416, a vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor, coadministered with bolus 5-fluorouracil (5-FU), leucovorin, and irinotecan (IFL) in untreated patients with metastatic colorectal cancer.
  
  
  METHODS
  SU5416 (85 or 145 mg/m2) was administered twice weekly throughout a 6-week period along with standard IFL (4 weeks on/2 weeks off). Plasma samples were assayed for SU5416, irinotecan, and SN-38 by reverse-phase HPLC. Contrast enhanced, color Doppler sonography was performed on patients at the MTD to identify changes in tumor perfusion.
  
  
  RESULTS
  Eleven patients received treatment with SU5416 85 mg/m2 (n = 5) or 145 mg/m2 (n = 6). At 85 mg/m2, no DLTs were observed. At 145 mg/m2, grade 3 diarrhea and vomiting were observed during cycle 1; other grade 3 toxicities included fatigue, nausea, anorexia, anemia, pain, urinary retention, and hypertension. The pharmacokinetics of irinotecan and SN-38 were not altered by coadministration of SU5416. SU5416 pharmacokinetics were not altered by IFL. Contrast-enhanced, color Doppler sonography was performed on 2 patients and demonstrated reduced tumor perfusion after treatment in a patient who responded to treatment and increased perfusion in a patient who developed progressive disease. Three patients (27%) had confirmed partial responses, 2 patients (18%) had unconfirmed partial responses, and 4 patients (36%) had stable disease.
  
  
  CONCLUSIONS
  Twice weekly SU5416 can be administered with bolus IFL without unexpected toxicities or altering the pharmacokinetic behavior of the administered drugs. Changes in tumor blood perfusion can be detected by contrast-enhanced, color Doppler sonography. The further development of SU5416 was halted before this study was completed.
authors.affiliation: Vanderbilt University Medical Center, Nashville, TN, USA. craig.lockhart@vanderbilt.edu
authors.forename: Albert Craig
authors.initials: AC
authors.lastname: Lockhart
authors.forename: Gillian F
authors.initials: GF
authors.lastname: Cropp
authors.forename: Jordan D
authors.initials: JD
authors.lastname: Berlin
authors.forename: Edwin
authors.initials: E
authors.lastname: Donnelly
authors.forename: Robert D
authors.initials: RD
authors.lastname: Schumaker
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Schaaf
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Hande
authors.forename: Arthur C
authors.initials: AC
authors.lastname: Fleischer
authors.forename: Alison L
authors.initials: AL
authors.lastname: Hannah
authors.forename: Mace L
authors.initials: ML
authors.lastname: Rothenberg
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011758:Pyrroles / Q000008:administration & dosage; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000502:physiology
chemical_list: D007211:Indoles; D011758:Pyrroles; C116890:Semaxinib; D000077146:Irinotecan; D040301:Vascular Endothelial Growth Factor Receptor-2; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin