title: A phase I study of liposomal-encapsulated docetaxel (LE-DT) in patients with advanced solid tumor malignancies.
abstract: BACKGROUND
  Docetaxel is a taxane anticancer drug used in a wide variety of solid tumors. Liposomes are versatile drug carriers that may increase drug solubility, serve as sustained release systems, provide protection from drug degradation and toxicities, and help overcome multidrug resistance. This phase I study was conducted to determine the maximum tolerated dose, dose-limiting toxicities (DLTs), pharmacokinetics (PK), and clinical response of liposomal-encapsulated docetaxel (LE-DT) in patients with advanced solid tumor malignancies.
  
  
  METHODS
  LE-DT was administered using a standard 3 + 3 dose escalation schema with dose levels of 50, 65, 85, 110, and 132 mg/m(2) IV on a 3-week cycle. Toxicities were assessed using the NCI-CTCAE version 3.0, and response was assessed using RECIST criteria (version 1.0). PK samples were drawn during cycle 1 and analyzed using a non-compartmental analysis.
  
  
  RESULTS
  Twenty-four patients were treated for 1-30 cycles (median = 4). No DLTs were experienced through dose levels of 50, 65, 85, and 110 mg/m(2). Two out of two patients experienced grade 4 neutropenia at the 132 mg/m(2) dose level. When an additional three patients were treated at the expanded 110 mg/m(2) dose level, two experienced grade 4 neutropenia. The 85 mg/m(2) dose level was reassessed with an expanded group of three additional patients, and only one of three patients experienced grade 4 neutropenia. The protocol was amended to allow G-CSF during cycle 1, and an additional three patients were treated at 110 mg/m(2) with no DLTs experienced. No patient experienced significant neuropathy, even patients treated for 19, 20, and 30 cycles. PK followed a two-compartment elimination pattern; there was no correlation between PK and toxicity. Two patients with thyroid and neuroendocrine cancer had partial responses (PR, 8%), and one patient with non-small-cell lung cancer had an unconfirmed PR. Eight patients (33%) had stable disease lasting more than 3 months, for a clinical benefit rate of 41%.
  
  
  CONCLUSIONS
  LE-DT was well tolerated with expected toxicities of neutropenia, anemia, and fatigue, but without neuropathy or edema. Clinical benefit (SD + PR) was observed in 41% of the patients. The recommended phase II dose of LE-DT is 85 mg/m(2) without G-CSF or 110 mg/m(2) with G-CSF.
authors.affiliation: Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3800 Reservoir Road, NW, Washington, DC 20007, USA. John.Deeken@gunet.georgetown.edu
authors.forename: John F
authors.initials: JF
authors.lastname: Deeken
authors.forename: Rebecca
authors.initials: R
authors.lastname: Slack
authors.forename: Glen J
authors.initials: GJ
authors.lastname: Weiss
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ramanathan
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Pishvaian
authors.forename: Jimmy
authors.initials: J
authors.lastname: Hwang
authors.forename: Karen
authors.initials: K
authors.lastname: Lewandowski
authors.forename: Deepa
authors.initials: D
authors.lastname: Subramaniam
authors.forename: Aiwu Ruth
authors.initials: AR
authors.lastname: He
authors.forename: Ion
authors.initials: I
authors.lastname: Cotarla
authors.forename: Aquilur
authors.initials: A
authors.lastname: Rahman
authors.forename: John L
authors.initials: JL
authors.lastname: Marshall
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000627:therapeutic use*; D019540:Area Under Curve; D015331:Cohort Studies; D000077143:Docetaxel; D004334:Drug Administration Schedule; D004337:Drug Carriers; D004339:Drug Compounding; D019008:Drug Resistance, Neoplasm; D005079:Excipients; D005260:Female; D005612:Freeze Drying; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008081:Liposomes; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D043823:Taxoids / Q000008:administration & dosage* / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D005079:Excipients; D008081:Liposomes; D043823:Taxoids; D000077143:Docetaxel