title: Phase I clinical trial of STA-4783 in combination with paclitaxel in patients with refractory solid tumors.
abstract: OBJECTIVE
  STA-4783 is a new compound that markedly enhances the therapeutic index of paclitaxel against human tumor xenograft models. A phase I clinical trial was undertaken to determine the maximum tolerated dose, toxicity profile, and pharmacokinetics of STA-4783 in combination with paclitaxel.
  
  
  METHODS
  Adults with refractory solid tumors concurrently received STA-4783 and paclitaxel as a 3-h i.v. infusion at starting doses of 44 and 135 mg/m(2), respectively. After increasing paclitaxel to 175 mg/m(2), the STA-4783 dose was escalated as permitted by dose-limiting toxicity during the first 21-day cycle.
  
  
  RESULTS
  Thirty-five patients were treated with eight dose levels of STA-4783/paclitaxel. In patients receiving 175 mg/m(2) paclitaxel, the incidence of severe toxicity increased with escalation of the STA-4783 dose above 263 mg/m(2), and 438 mg/m(2) was the maximum tolerated dose. All toxicities were typical of paclitaxel, with neutropenia, mucositis, and myalgia/arthralgia being dose limiting. Partial responses were achieved in one patient with Kaposi's sarcoma and another with ovarian cancer that progressed during prior treatment with paclitaxel. STA-4783 exhibited linear pharmacokinetics characterized by rapid elimination from plasma (biological half-life, 1.06 +/- 0.24 h) and a low steady-state apparent volume of distribution (25.1 +/- 8.1 L/m(2)). The total body clearance of paclitaxel decreased significantly with escalation of the STA-4783 dose.
  
  
  CONCLUSIONS
  The STA-4783/paclitaxel combination was well tolerated with a toxicity profile similar to single-agent paclitaxel. Enhanced systemic exposure to paclitaxel resulting from a dose-dependent interaction with STA-4783 was associated with increased toxicity. Objective responses in two heavily pretreated patients, both with taxane exposure, have encouraged further clinical evaluation of this regimen.
authors.affiliation: Beth Israel Deaconess Medical Center, and Harvard Cancer Center, Boston, MA, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Berkenblit
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Eder
authors.forename: David P
authors.initials: DP
authors.lastname: Ryan
authors.forename: Michael V
authors.initials: MV
authors.lastname: Seiden
authors.forename: Noriaki
authors.initials: N
authors.lastname: Tatsuta
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Sherman
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Dahl
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Dezube
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Supko
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006801:Humans; D006834:Hydrazines / Q000008:administration & dosage*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D008956:Models, Chemical; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D006834:Hydrazines; C512195:elesclomol; D017239:Paclitaxel