title: A Phase I trial of H-ras antisense oligonucleotide ISIS 2503 administered as a continuous intravenous infusion in patients with advanced carcinoma.
abstract: BACKGROUND
  Abnormal expression of Ras proteins frequently is found with oncogenic transformation making ras a promising therapeutic target. ISIS 2503 is a 20-base antisense phosphorothioate oligodeoxyribonucleotide that specifically downregulates H-ras expression and inhibits tumor cell growth in preclinical studies. Here, the authors report an initial clinical study of the safety and tolerability of an intravenous infusion of ISIS 2503 in patients with advanced cancer.
  
  
  METHODS
  A continuous intravenous infusion of ISIS 2503 was administered for 14 days every 3 weeks to 23 patients with a variety of solid tumors refractory to standard therapy. The dose of ISIS 2503 was increased in sequential cohorts of patients, as toxicity allowed, until a final dose of 10.0 mg/kg/day of body weight was reached. Toxicity was scored by the National Cancer Institute's Common Toxicity Criteria, and tumor response was monitored after every two treatment cycles. Pharmacokinetic studies were performed in some of the patients up to, and including, the final dose of 10 mg/kg/day/day of body weight. Levels of H-ras mRNA expression also were determined in the circulating lymphocytes of some patients by quantitative reverse transcriptase-polymerase chain reaction.
  
  
  RESULTS
  A total of 23 patients received 63 cycles of ISIS 2503 at escalating doses to 10.0 mg/kg/day without dose-limiting toxicity and only minimal side effects. Four patients had stabilization of their disease for 6-10 cycles. No consistent decreases in H-ras mRNA levels were observed in peripheral blood lymphocytes.
  
  
  CONCLUSIONS
  ISIS 2503, an antisense oligonucleotide against H-ras, was well tolerated as a single agent at doses up to 10.0 mg/kg/day by 14-day continuous intravenous infusion. Several patients had stabilization of disease, suggesting that ISIS 2503 had some tumor growth inhibitory effects and future trials of ISIS 2503 in combination with chemotherapy should be considered.
authors.affiliation: U.S. Oncology, Dallas, Texas, USA. Casey.Cunningham@usoncology.com
authors.forename: C C
authors.initials: CC
authors.lastname: Cunningham
authors.forename: J T
authors.initials: JT
authors.lastname: Holmlund
authors.forename: R S
authors.initials: RS
authors.lastname: Geary
authors.forename: T J
authors.initials: TJ
authors.lastname: Kwoh
authors.forename: A
authors.initials: A
authors.lastname: Dorr
authors.forename: J F
authors.initials: JF
authors.lastname: Johnston
authors.forename: B
authors.initials: B
authors.lastname: Monia
authors.forename: J
authors.initials: J
authors.lastname: Nemunaitis
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002277:Carcinoma / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D011905:Genes, ras; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D054735:Phosphorothioate Oligonucleotides; D012333:RNA, Messenger / Q000097:blood
chemical_list: D000970:Antineoplastic Agents; C122000:ISIS 2503; D016376:Oligonucleotides, Antisense; D054735:Phosphorothioate Oligonucleotides; D012333:RNA, Messenger