title: A phase IB clinical and pharmacokinetic study of the angiogenesis inhibitor SU5416 and paclitaxel in recurrent or metastatic carcinoma of the head and neck.
abstract: OBJECTIVE
  SU5416 is a novel small organic molecule that non-competitively inhibits the phosphorylation of the VEGF tyrosine kinase receptor, Flk-1. This phase IB study was performed to determine the safety, pharmacokinetics, and preliminary efficacy of the combination of SU5416 and paclitaxel in recurrent or metastatic carcinoma of the head and neck.
  
  
  METHODS
  Enrolled in the study were 12 patients with biopsy-proven recurrent or metastatic carcinoma of the head and neck. Six patients received intravenous SU5416 110 mg/m2 on days 1, 15, 18, 22 and 25, and paclitaxel 70 mg/m2 on days 8, 15 and 22. Since two patients experienced a dose-limiting toxicity (DLT) in cohort 1, the next six patients received identical treatment as above except the paclitaxel dose was reduced to 55 mg/m2 per week.
  
  
  RESULTS
  A total of 42 cycles at two different dose levels were given. In cohort 1 there were two deep venous thromboses that were DLTs. In the second cohort there was a DLT consisting of a transient ischemic attack after receiving SU5416. Most of the other toxicities seen were grade 1 or 2 in nature and consisted of headache, facial flushing, and fatigue. Two patients developed extensive ulcerative cavities at sites of prior radiation. There were no significant changes in the pharmacokinetic parameters of SU5416 given with paclitaxel. Four patients had prolonged freedom from progression of 18, 28, 42, and 60 weeks duration.
  
  
  CONCLUSIONS
  The combination of SU5416 with paclitaxel had a higher than expected incidence of thromboembolic events and prophylactic anticoagulation should be considered for future trials that combine an angiogenesis inhibitor with cytotoxic chemotherapy. Although the future development of SU5416 as a chemotherapeutic agent is unclear, there was a clinical benefit seen with this combination in 36% of the patients. This trial supports the use of developing antiangiogenic combinations, using molecular targeted agents, in head and neck carcinoma.
authors.affiliation: Developmental Therapeutics Program, CASE Comprehensive Cancer Center, University Hospitals of Cleveland, 211100 Euclid Avenue, Cleveland, OH, 44106, USA. matthew.cooney@uhhs.com
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Cooney
authors.forename: Kou-Yi
authors.initials: KY
authors.lastname: Tserng
authors.forename: Vinit
authors.initials: V
authors.lastname: Makar
authors.forename: R Jeff
authors.initials: RJ
authors.lastname: McPeak
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Ingalls
authors.forename: Afshin
authors.initials: A
authors.lastname: Dowlati
authors.forename: Beth
authors.initials: B
authors.lastname: Overmoyer
authors.forename: Keith
authors.initials: K
authors.lastname: McCrae
authors.forename: Pamela
authors.initials: P
authors.lastname: Ksenich
authors.forename: Pierre
authors.initials: P
authors.lastname: Lavertu
authors.forename: Percy
authors.initials: P
authors.lastname: Ivy
authors.forename: Charles L
authors.initials: CL
authors.lastname: Hoppel
authors.forename: Scot
authors.initials: S
authors.lastname: Remick
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D011758:Pyrroles; C116890:Semaxinib; D017239:Paclitaxel