title: Phase I and pharmacologic study of liposomal lurtotecan, NX 211: urinary excretion predicts hematologic toxicity.
abstract: OBJECTIVE
  To determine the maximum-tolerated and recommended dose, toxicity profile, and pharmacokinetics of the liposomal topoisomerase I inhibitor lurtotecan (NX 211) administered as a 30-minute intravenous infusion once every 3 weeks in cancer patients.
  
  
  METHODS
  NX 211 was administered by peripheral infusion. Dose escalation decisions were based on all toxicities during the first cycle as well as pharmacokinetic parameters. Serial plasma, whole blood, and urine samples were collected for up to 96 hours after the end of infusion, and drug levels were determined by high-performance liquid chromatography.
  
  
  RESULTS
  Twenty-nine patients (16 women; median age, 56 years; range, 39 to 74 years) received 77 courses of NX 211 at dose levels of 0.4 (n = 3), 0.8 (n = 6), 1.6 (n = 3), 3.2 (n = 6), 3.8 (n = 6), and 4.3 mg/m(2) (n = 5). Neutropenia and thrombocytopenia were the dose-limiting toxicities and were not cumulative. Other toxicities were mild to moderate. Nine patients had stable disease while undergoing treatment. The systemic clearance of lurtotecan in plasma and whole blood was 0.82 +/- 0.78 L/h/m(2) and 1.15 +/- 0.96 L/h/m(2), respectively. Urinary recovery (Fu) of lurtotecan was 10.1% +/- 4.05% (range, 4.9% to 18.9%). In contrast to systemic exposure measures, the dose excreted in urine (ie, dose x Fu) was significantly related to the percent decrease in neutrophil and platelet counts at nadir (P <.00001).
  
  
  CONCLUSIONS
  The dose-limiting toxicities of NX 211 are neutropenia and thrombocytopenia. The recommended dose for phase II studies is 3.8 mg/m(2) once every 3 weeks. Pharmacologic data suggest a relationship between exposure to lurtotecan and NX 211-induced clinical effects.
authors.affiliation: Department of Medical Oncology, Rotterdam Cancer Institute, Daniel den Hoed Kliniek and University Hospital, Rotterdam, The Netherlands. diederikkeher@hotmail.com
authors.forename: Diederik F S
authors.initials: DF
authors.lastname: Kehrer
authors.forename: Annelies M
authors.initials: AM
authors.lastname: Bos
authors.forename: Jaap
authors.initials: J
authors.lastname: Verweij
authors.forename: Harry J
authors.initials: HJ
authors.lastname: Groen
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Loos
authors.forename: Alex
authors.initials: A
authors.lastname: Sparreboom
authors.forename: Maja J A
authors.initials: MJ
authors.lastname: de Jonge
authors.forename: Marta
authors.initials: M
authors.lastname: Hamilton
authors.forename: Terri
authors.initials: T
authors.lastname: Cameron
authors.forename: Elisabeth G E
authors.initials: EG
authors.lastname: de Vries
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity* / Q000652:urine; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000633:toxicity* / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D013921:Thrombocytopenia / Q000139:chemically induced
chemical_list: D000970:Antineoplastic Agents; C091719:lurtotecan; D002166:Camptothecin