title: A phase I, pharmacokinetic and biologic correlative study of oblimersen sodium (Genasense, G3139) and irinotecan in patients with metastatic colorectal cancer.
abstract: OBJECTIVE
  To assess the feasibility and antitumor activity of oblimersen sodium, an antisense oligonucleotide directed to the Bcl-2 mRNA, combined with irinotecan in patients with advanced colorectal carcinoma, characterize the pharmacokinetic behavior of both oblimersen sodium and irinotecan, and examine Bcl-2 protein inhibition in peripheral blood mononuclear cells (PBMC).
  
  
  METHODS
  Patients were treated with escalating doses of oblimersen sodium administered by continuous intravenous infusion (CIVI) days 1-8, and irinotecan administered intravenously on day 6 once every 3 weeks.
  
  
  RESULTS
  Twenty patients received a total of 84 courses at doses ranging from 3 to 7 mg/kg/day for oblimersen sodium and from 280 to 350 mg/m2 for irinotecan. Febrile neutropenia and diarrhea limited escalation of oblimersen sodium and irinotecan to 5 mg/kg/day and 350 mg/m2, respectively. Other toxicities included nausea, vomiting, fever and fatigue. Steady-state plasma concentrations were achieved within 48 h of beginning oblimersen sodium treatment and the agent was undetectable 24 h after the discontinuation of the infusion. Reduction in levels of Bcl-2 protein in PBMC was documented following treatment with oblimersen sodium. One patient experienced a partial response and 10 additional patients had stable disease lasting 2.5-10 months.
  
  
  CONCLUSIONS
  The combination is well tolerated at the recommended phase II oblimersen sodium dose of 7 mg/kg/day CIVI days 1-8 with irinotecan 280 mg/m2 intravenously on day 6 every 3 weeks.
authors.affiliation: Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX 78229, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Mita
authors.forename: L
authors.initials: L
authors.lastname: Ochoa
authors.forename: E K
authors.initials: EK
authors.lastname: Rowinsky
authors.forename: J
authors.initials: J
authors.lastname: Kuhn
authors.forename: G
authors.initials: G
authors.lastname: Schwartz
authors.forename: L A
authors.initials: LA
authors.lastname: Hammond
authors.forename: A
authors.initials: A
authors.lastname: Patnaik
authors.forename: I-T
authors.initials: IT
authors.lastname: Yeh
authors.forename: E
authors.initials: E
authors.lastname: Izbicka
authors.forename: K
authors.initials: K
authors.lastname: Berg
authors.forename: A W
authors.initials: AW
authors.lastname: Tolcher
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005260:Female; D006801:Humans; D000077146:Irinotecan; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008231:Lymphopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009503:Neutropenia / Q000139:chemically induced; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000493:pharmacokinetics*; D013873:Thionucleotides / Q000235:genetics / Q000493:pharmacokinetics*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004338:Drug Combinations; D016376:Oligonucleotides, Antisense; D013873:Thionucleotides; D000077146:Irinotecan; C408162:oblimersen; D002166:Camptothecin