title: A phase II study of the antisense oligonucleotide GTI-2040 plus docetaxel and prednisone as first-line treatment in castration-resistant prostate cancer.
abstract: OBJECTIVE
  GTI-2040 is a novel antisense oligonucleotide to the R2 subunit of ribonucleotide reductase. This phase II trial was conducted to determine the efficacy and tolerability of GTI-2040 when combined with docetaxel and prednisone for the treatment of patients with castration-resistant prostate cancer (CRPC).
  
  
  METHODS
  Chemo-naïve CRPC patients with adequate performance status and organ function were treated with docetaxel 75 mg/m(2) IV on day 1 plus GTI-2040 5 mg/kg/day by continuous intravenous infusion day 1-14 on a 21 day cycle, with prednisone 5 mg orally twice daily. The primary endpoint was PSA response rate. Pharmacokinetic studies of GTI-2040 and pharmacodynamic studies on peripheral blood mononuclear cells (PBMC) were also performed.
  
  
  RESULTS
  Twenty-two patients in total (19 from this study and 3 from a prior phase I/II study at this institution) were treated at the recommended phase II dose. A confirmed PSA response was seen in 9/22 patients (41%). Of 16 patients with measurable disease, there was 1 partial response (PR) and 12 stable disease (SD) lasting 3.6 months (median), as best response. The most common toxicities were anemia, fatigue, lymphopenia, leucopenia and neutropenia. Grade 3+ toxicities included neutropenia, lymphopenia, leucopenia, fatigue, febrile neutropenia and hypophosphatemia.
  
  
  CONCLUSIONS
  The PSA response rate of GTI-2040 in combination with docetaxel and prednisone just met the minimum phase II criteria for further enrollment. However, after evaluation of all the clinical data, further study of this dose and schedule of GTI-2040 in CRPC was not recommended.
authors.affiliation: Princess Margaret Hospital, Phase II Consortium, University of Toronto, 610 University Avenue, Suite 5-222, Toronto, ON M5G 2M9, USA. srikala.sridhar@uhn.on.ca
authors.forename: Srikala S
authors.initials: SS
authors.lastname: Sridhar
authors.forename: Christina M
authors.initials: CM
authors.lastname: Canil
authors.forename: Kim N
authors.initials: KN
authors.lastname: Chi
authors.forename: Sebastien J
authors.initials: SJ
authors.lastname: Hotte
authors.forename: Scott
authors.initials: S
authors.lastname: Ernst
authors.forename: Lisa
authors.initials: L
authors.lastname: Wang
authors.forename: Eric X
authors.initials: EX
authors.lastname: Chen
authors.forename: Agnes
authors.initials: A
authors.lastname: Juhasz
authors.forename: Yun
authors.initials: Y
authors.lastname: Yen
authors.forename: Peter
authors.initials: P
authors.lastname: Murray
authors.forename: James A
authors.initials: JA
authors.lastname: Zwiebel
authors.forename: Malcolm J
authors.initials: MJ
authors.lastname: Moore
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000077143:Docetaxel; D005500:Follow-Up Studies; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage; D009919:Orchiectomy; D011241:Prednisone / Q000008:administration & dosage; D017430:Prostate-Specific Antigen / Q000097:blood*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D043823:Taxoids / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D009838:Oligodeoxyribonucleotides; D043823:Taxoids; D000077143:Docetaxel; C464617:GTI2040; D017430:Prostate-Specific Antigen; D011241:Prednisone