title: A phase I, dose escalation trial of ZD0473, a novel platinum analogue, in combination with gemcitabine.
abstract: OBJECTIVE
  To develop a combination regimen for clinical testing, we performed a dose escalation study of ZD0473 in combination with gemcitabine. ZD0473 is a novel platinum analogue with an aliphatic cyclic carrier ligand. In vitro and in vivo studies suggest that it possesses a different spectrum of antitumor activity from cisplatin and carboplatin. In single-agent studies of ZD0473, myelosuppression was the predominant toxicity and responses wer observed.
  
  
  METHODS
  In this combination phase I trial, 36 patients with advanced cancer were accrued to four dose levels, with doses of ZD0473 and gemcitabine ranging from 60 to 120 mg/m2 and 600 to 750 mg/m2, respectively ZD0473 was administered on day 1 and gemcitabine was given on days 1 and 8 of a 21-day cycle.
  
  
  RESULTS
  Hematologic toxicity was dose-limiting. Grade 3 and 4 thrombocytopenia and neutropenia occurred during 60% and 41% of all cycles. Nonhematologic toxicities were mild and reversible. Two partial responses and 19 patients with stable disease were observed.
  
  
  CONCLUSIONS
  The recommended phase II doses are 90 mg/m2 of ZD0473 and 750 mg/m2 of gemcitabine for lightly pretreated patients and 600 mg/m2 for heavily pretreated patients. The combination of ZD0473 and gemcitabine is associated with dose-dependent thrombocytopenia and neutropenia as well as having promising clinical activity.
authors.affiliation: Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA 19104, USA. ktflaherty@aol.com
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.forename: James P
authors.initials: JP
authors.lastname: Stevenson
authors.forename: Maryann
authors.initials: M
authors.lastname: Redlinger
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Algazy
authors.forename: Bruce
authors.initials: B
authors.lastname: Giatonio
authors.forename: Peter J
authors.initials: PJ
authors.lastname: O'Dwyer
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002648:Child; D003841:Deoxycytidine / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives*; D005260:Female; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000188:drug therapy*; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D000093542:Gemcitabine
chemical_list: D009944:Organoplatinum Compounds; C110525:amminedichloro(2-methylpyridine)platinum(II); D003841:Deoxycytidine; D000093542:Gemcitabine