title: A Phase I/II study of GTI-2040 and capecitabine in patients with renal cell carcinoma.
abstract: BACKGROUND
  Fluoropyrimidine based therapy has modest activity in patients with metastatic renal carcinoma and inhibition of ribonucleotide reductase is synergistic in model systems. GTI-2040 is a 20-mer phosphorothioate oligonucleotide complimentary to the R2 component of ribonucleotide reductase that has activity in renal cancer models.
  
  
  METHODS
  Metastatic renal carcinoma patients without prior fluoropyrimidine therapy and normal organ function were treated with oral capecitabine 880 mg/m(2) twice daily along with continuous infusion GTI-2040 starting at 148 mg/m(2)/day for 21 days, for each 28-day cycle. After completion of the phase I portion, the phase II study portion sought to rule out a null hypothesized 10% response rate versus an alternative 25% response rate utilizing alpha and beta errors of 0.05 and 0.2, respectively. GTI-2040 pharmacokinetics and effects on ribonucleotide reductase expression in peripheral mononuclear cells were evaluated in a subset of patients.
  
  
  RESULTS
  Based on one dose limiting toxicity in nine patients in the phase I portion, the phase II portion was conducted using the previously recommended 185 mg/m(2)/day dose of GTI-2040. Twenty-six patients were enrolled in the phase II portion to obtain 18 fully evaluable for response. Only one patient, treated at a GTI 2040 dose of 185 mg/m(2)/day in the phase I portion of the protocol, responded. Toxicities and GTI-2040 pharmacokinetics were consistent with previously reported results. R2 expression in peripheral mononuclear cells was too variable for accurate interpretation.
  
  
  CONCLUSIONS
  Further study of GTI-2040 and capecitabine in metastatic renal cancer at this dose and schedule is not indicated. Further study is necessary to determine whether lack of activity is due to inadequate target inhibition or inadequate effect of appropriate targeting.
authors.affiliation: Department of Medicine, Section of Hematology/Oncology and Urology, University of Chicago, 5841 S. Maryland Ave, MC-2115, Chicago, IL 60637, USA. wstadler@medicine.bsd.uchicago.edu
authors.forename: Walter M
authors.initials: WM
authors.lastname: Stadler
authors.forename: Apurva A
authors.initials: AA
authors.lastname: Desai
authors.forename: David I
authors.initials: DI
authors.lastname: Quinn
authors.forename: Ronald
authors.initials: R
authors.lastname: Bukowski
authors.forename: Bernard
authors.initials: B
authors.lastname: Poiesz
authors.forename: Carl G
authors.initials: CG
authors.lastname: Kardinal
authors.forename: Nancy
authors.initials: N
authors.lastname: Lewis
authors.forename: Alex
authors.initials: A
authors.lastname: Makalinao
authors.forename: Peter
authors.initials: P
authors.lastname: Murray
authors.forename: Frank M
authors.initials: FM
authors.lastname: Torti
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000069287:Capecitabine; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018450:Disease Progression; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D007262:Infusions, Intravenous; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D009838:Oligodeoxyribonucleotides; D003841:Deoxycytidine; C464617:GTI2040; D000069287:Capecitabine; D005472:Fluorouracil