title: A phase II, pharmacokinetic, and biological correlative study of oblimersen sodium and docetaxel in patients with hormone-refractory prostate cancer.
abstract: OBJECTIVE
  To determine the antitumor activity and safety of oblimersen sodium, a phosphorothioate antisense oligonucleotide directed to the bcl-2 mRNA, with docetaxel in patients with hormone-refractory prostate cancer (HRPC) and to determine if relevant pharmacokinetic and pharmacodynamic variables of oblimersen or docetaxel influence response to this therapy.
  
  
  METHODS
  Patients with HRPC were treated with oblimersen sodium by continuous i.v. infusion on days 1 to 8 with docetaxel given i.v. over 1 hour on day 6 every 3 weeks. Plasma samples were analyzed to characterize the pharmacokinetic variables of both oblimersen and docetaxel, and paired collections of peripheral blood mononuclear cells were collected to determine Bcl-2 protein expression pretreatment and post-treatment.
  
  
  RESULTS
  Twenty-eight patients received 173 courses of oblimersen (7 mg/kg/d continuous i.v. infusion on days 1-8) and docetaxel (75 mg/m(2) i.v. on day 6). Prostate-specific antigen responses were observed in 14 of 27 (52%) patients, whereas 4 of 12 (33%) patients with bidimensionally measurable disease had objective responses. The mean oblimersen steady-state concentration (C(ss)) was a significant determinant of antitumor activity; mean C(ss) values were higher in responders compared with nonresponders (6.24 +/- 1.68 versus 4.27 +/- 1.22; P = 0.008). The median survival of all patients was 19.8 months. Bcl-2 protein expression decreased a median of 49.9% in peripheral blood mononuclear cells post-treatment, but the individual incremental change did not correlate with either oblimersen C(ss) or response.
  
  
  CONCLUSIONS
  Oblimersen combined with docetaxel is an active combination in HRPC patients demonstrating both an encouraging response rate and an overall median survival. The absence of severe toxicities at this recommended dose, evidence of Bcl-2 protein inhibition, and encouraging antitumor activity in HPRC patients warrant further clinical evaluation of this combination, including studies to optimize oblimersen C(ss).
authors.affiliation: Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, Texas, USA. atolcher@idd.org
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
authors.forename: Kim
authors.initials: K
authors.lastname: Chi
authors.forename: John
authors.initials: J
authors.lastname: Kuhn
authors.forename: Martin
authors.initials: M
authors.lastname: Gleave
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
authors.forename: Chris
authors.initials: C
authors.lastname: Takimoto
authors.forename: Garry
authors.initials: G
authors.lastname: Schwartz
authors.forename: Ian
authors.initials: I
authors.lastname: Thompson
authors.forename: Kristin
authors.initials: K
authors.lastname: Berg
authors.forename: Susan
authors.initials: S
authors.lastname: D'Aloisio
authors.forename: Nevin
authors.initials: N
authors.lastname: Murray
authors.forename: Stanley R
authors.initials: SR
authors.lastname: Frankel
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Izbicka
authors.forename: Eric
authors.initials: E
authors.lastname: Rowinsky
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D008875:Middle Aged; D016376:Oligonucleotides, Antisense; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D016019:Survival Analysis; D043823:Taxoids / Q000008:administration & dosage / Q000493:pharmacokinetics; D013873:Thionucleotides / Q000008:administration & dosage / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D043823:Taxoids; D013873:Thionucleotides; D000077143:Docetaxel; C408162:oblimersen