title: A phase I study of intraperitoneal nanoparticulate paclitaxel (Nanotax®) in patients with peritoneal malignancies.
abstract: OBJECTIVE
  This multicenter, open-label, dose-escalating, phase I study evaluated the safety, tolerability, pharmacokinetics and preliminary tumor response of a nanoparticulate formulation of paclitaxel (Nanotax®) administered intraperitoneally for multiple treatment cycles in patients with solid tumors predominantly confined to the peritoneal cavity for whom no other curative systemic therapy treatment options were available.
  
  
  METHODS
  Twenty-one patients with peritoneal malignancies received Nanotax® in a modified dose-escalation approach utilizing an accelerated titration method. All patients enrolled had previously received chemotherapeutics and undergone surgical procedures, including 33 % with optimal debulking. Six doses (50-275 mg/m(2)) of Cremophor-free Nanotax® were administered intraperitoneally for one to six cycles (every 28 days).
  
  
  RESULTS
  Intraperitoneal (IP) administration of Nanotax® did not lead to increases in toxicity over that typically associated with intravenous (IV) paclitaxel. No patient reported ≥Grade 2 neutropenia and/or ≥Grade 3 neurologic toxicities. Grade 3 thrombocytopenia unlikely related to study medication occurred in one patient. The peritoneal concentration-time profile of paclitaxel rose during the 2 days after dosing to peritoneal fluid concentrations 450-2900 times greater than peak plasma drug concentrations and remained elevated through the entire dose cycle. Best response assessments were made in 16/21 patients: Four patients were assessed as stable or had no response and twelve patients had increasing disease. Five of 21 patients with advanced cancers survived longer than 400 days after initiation of Nanotax® IP treatment.
  
  
  CONCLUSIONS
  Compared to IV paclitaxel administration, Cremophor-free IP administration of Nanotax® provides higher and prolonged peritoneal paclitaxel levels with minimal systemic exposure and reduced toxicity.
authors.affiliation: University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA, swilliam@kumc.edu.
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Williamson
authors.forename: Gary A
authors.initials: GA
authors.lastname: Johnson
authors.forename: Holly A
authors.initials: HA
authors.lastname: Maulhardt
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Moore
authors.forename: D S
authors.initials: DS
authors.lastname: McMeekin
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Schulz
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Reed
authors.forename: Katherine F
authors.initials: KF
authors.lastname: Roby
authors.forename: Christine B
authors.initials: CB
authors.lastname: Mackay
authors.forename: Holly J
authors.initials: HJ
authors.lastname: Smith
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Weir
authors.forename: Jo A
authors.initials: JA
authors.lastname: Wick
authors.forename: Maurie
authors.initials: M
authors.lastname: Markman
authors.forename: Gere S
authors.initials: GS
authors.lastname: diZerega
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Baltezor
authors.forename: Jahna
authors.initials: J
authors.lastname: Espinosa
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Decedue
mesh_terms: D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007263:Infusions, Parenteral; D008297:Male; D008875:Middle Aged; D053758:Nanoparticles / Q000008:administration & dosage* / Q000009:adverse effects* / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D017239:Paclitaxel