title: A phase I trial of intraperitoneal sustained-release paclitaxel microspheres (Paclimer) in recurrent ovarian cancer: a Gynecologic Oncology Group study.
abstract: OBJECTIVE
  Paclimer is a biodegradable polymer microsphere formulation containing 10% (w/w) paclitaxel that is designed to provide a sustained-release form of paclitaxel after intraperitoneal (IP) administration. The goals of this phase I study were to determine the maximum tolerated dose (MTD) of IP paclitaxel microspheres and the pharmacology of paclitaxel after IP paclitaxel microsphere administration.
  
  
  METHODS
  Twelve patients with recurrent or persistent ovarian or primary peritoneal carcinoma were treated. After placement of an IP catheter, patients were treated with escalating doses of IP paclitaxel microspheres administered with 2 l of normal saline following premedication. Treatment could be repeated once, 8 weeks after initial treatment. The starting dose was 60 mg/m2 and no intrapatient dose escalation was used.
  
  
  RESULTS
  One dose-limiting toxicity consisting of abdominal pain, ileus and bowel obstruction was seen with the second cycle of therapy in one patient who received 900 mg/m2. Patients received up to 1200 mg/m2 without further evidence of dose-limiting toxicities (DLT). The study was discontinued before MTD was defined due to the manufacturer's decision to suspend further clinical development of paclitaxel microspheres. Pharmacokinetic analysis showed a trend toward a dose-dependent effect of IP paclitaxel microspheres on measured plasma paclitaxel levels. Sustained paclitaxel levels were maintained throughout all 8 weeks of therapy; however, paclitaxel concentrations were well below the plasma concentrations associated with toxicity. In one patient, laparoscopy revealed extensive adhesions, fat necrosis, foreign body giant cell reaction and detectable residual polymer filaments 7 months after completion of treatment with paclitaxel microspheres.
  
  
  CONCLUSIONS
  IP administration of paclitaxel microspheres is well tolerated up to 1200 mg/m2 without defining MTD. The low but persistent detection of plasma paclitaxel indicates that paclitaxel continues to be released for at least 8 weeks after IP paclitaxel microsphere treatment. The finding of significant peritoneal abnormalities, including the presence of residual polymer filaments, months after IP Paclimer treatment suggests that the polymer preparation used in Paclimer degrades slowly.
authors.affiliation: John Hopkins Kimmel Cancer Center, Bunting Blaustein Cancer Research Building, Baltimore, MD 21231-1000, USA. darmstro@welchlink.welch.jhu.edu
authors.forename: Deborah K
authors.initials: DK
authors.lastname: Armstrong
authors.forename: Gini F
authors.initials: GF
authors.lastname: Fleming
authors.forename: Maurie
authors.initials: M
authors.lastname: Markman
authors.forename: Howard H
authors.initials: HH
authors.lastname: Bailey
mesh_terms: D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D003692:Delayed-Action Preparations; D005260:Female; D006801:Humans; D007263:Infusions, Parenteral; D008863:Microspheres; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D003692:Delayed-Action Preparations; C485024:polilactofate; D017239:Paclitaxel