title: A phase I study of AMD473 and docetaxel given once every 3 weeks in patients with advanced refractory cancer: a National Cancer Institute of Canada-Clinical Trials Group trial, IND 131.
abstract: BACKGROUND
  AMD473 (previously ZD0473) is a new-generation platinum compound with activity against a wide range of human tumour cell lines and xenografts, including carboplatin- and cisplatin-resistant lines. To assess its potential combined with a taxane, a phase I study of AMD473 and docetaxel in advanced cancer was initiated by the National Cancer Institute of Canada-Clinical Trials Group.
  
  
  METHODS
  Patients with advanced cancer, measurable disease, performance status Eastern Cooperative Oncology Group 0-2, no major organ dysfunction, and one or no previous taxane regimen received escalating doses of AMD473 and docetaxel every 3 weeks, with a starting dose of AMD473 80 mg/m(2) and docetaxel 60 mg/m(2).
  
  
  RESULTS
  Thirty-three patients enrolled on four dose levels were evaluable for toxicity and 25 patients were evaluable for response. The maximum tolerated dose was dose level 4 (AMD473 120 mg/m(2) and docetaxel 75 mg/m(2)), with grade 4 neutropenia in both minimally and heavily pretreated patients causing dose-limiting toxicity. As well at dose level 4, one patient had grade 3 vomiting despite premedication. Dose level three was expanded for both groups of patients and was defined as the recommended phase II dose at AMD473 100 mg/m(2) and docetaxel 75 mg/m(2). Non-hematologic toxicities included fatigue, diarrhoea and other mild toxicities. There was one partial response in a patient with prostate cancer and stable disease in 15 patients. No apparent pharmacokinetic interaction was noted.
  
  
  CONCLUSIONS
  AMD473 and docetaxel can be combined with a recommended phase II dose level of 100 mg/m(2) and 75 mg/m(2), respectively, given intravenously every 3 weeks. The combination has activity and should be explored in responsive tumour types.
authors.affiliation: British Columbia Cancer Agency, Vancouver Cancer Centre, Vancouver, BC. kgelmon@bccancer.bc.ca
authors.forename: K A
authors.initials: KA
authors.lastname: Gelmon
authors.forename: D
authors.initials: D
authors.lastname: Stewart
authors.forename: K N
authors.initials: KN
authors.lastname: Chi
authors.forename: S
authors.initials: S
authors.lastname: Chia
authors.forename: C
authors.initials: C
authors.lastname: Cripps
authors.forename: S
authors.initials: S
authors.lastname: Huan
authors.forename: S
authors.initials: S
authors.lastname: Janke
authors.forename: D
authors.initials: D
authors.lastname: Ayers
authors.forename: D
authors.initials: D
authors.lastname: Fry
authors.forename: J A
authors.initials: JA
authors.lastname: Shabbits
authors.forename: W
authors.initials: W
authors.lastname: Walsh
authors.forename: L
authors.initials: L
authors.lastname: McIntosh
authors.forename: L K
authors.initials: LK
authors.lastname: Seymour
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D018288:Carcinoma, Small Cell / Q000188:drug therapy; D015331:Cohort Studies; D003967:Diarrhea / Q000139:chemically induced; D000077143:Docetaxel; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D018307:Neoplasms, Squamous Cell / Q000188:drug therapy; D009503:Neutropenia / Q000139:chemically induced; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood; D011471:Prostatic Neoplasms / Q000188:drug therapy; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood; D016896:Treatment Outcome
chemical_list: D009944:Organoplatinum Compounds; D043823:Taxoids; C110525:amminedichloro(2-methylpyridine)platinum(II); D000077143:Docetaxel