Phase I trial of BCL-2 antisense oligonucleotide (G3139) administered by continuous intravenous infusion in patients with advanced cancer Journal Article


Authors: Morris, M. J.; Tong, W. P.; Cordon-Cardo, C.; Drobnjak, M.; Kelly, W. K.; Slovin, S. F.; Terry, K. L.; Siedlecki, K.; Swanson, P.; Rafi, M.; DiPaola, R. S.; Rosen, N.; Scher, H. I.
Article Title: Phase I trial of BCL-2 antisense oligonucleotide (G3139) administered by continuous intravenous infusion in patients with advanced cancer
Abstract: Purpose: To evaluate the safety and pharmacokinetics of BCL-2 antisense oligonucleotide (G3139) administered by prolonged i.v. infusion in patients with advanced cancer. Experimental Design: A total of 35 patients was treated in cohorts of 3-6 with 0.6-6.9 mg/kg/day of BCL-2 antisense oligonucleotide as a continuous infusion for 14 or 21 days. Plasma levels of intact antisense oligonucleotide were measured in all patients. Results: G3139 was generally well tolerated. At the highest dose level examined in this study (6.9 mg/kg/day), fatigue and transient reversible elevations of serum transaminases (grades 2-3) became apparent after ≥7 days of treatment. Both reactions were believed to be drug related. Pharmacokinetic analyses showed that steady-state plasma concentrations of G3139 were reached ∼10 h after starting the infusion and increased linearly across the range of doses administered ≤6.9 mg/kg/day. The terminal plasma half-life was ∼2 h. Exploratory studies using Western blots, performed on peripheral blood mononuclear cells on selected patients, demonstrated a decline in bcl-2 protein levels during treatment. No major antitumor responses were observed. Conclusions: BCL-2 antisense therapy is well tolerated. Relative to other dose-finding studies of G3139, fatigue was somewhat more prominent in this study, possibly because of the protracted i.v. infusion schedule of the antisense oligonucleotide. Current randomized trials are using the highest daily dose established in this study given by shorter infusion periods (i.e., 7 mg/kg/day for 5-7 days) to enhance the antitumor activity of standard cytotoxic drugs.
Keywords: adult; clinical article; controlled study; human tissue; protein expression; aged; aged, 80 and over; middle aged; human cell; clinical trial; drug activity; drug tolerability; fatigue; advanced cancer; diarrhea; dose response; drug efficacy; antineoplastic agents; neoplasms; cancer immunotherapy; controlled clinical trial; infection; liver toxicity; cohort studies; steady state; thrombocytopenia; bone pain; continuous infusion; dose-response relationship, drug; abdominal pain; dyspnea; hyperglycemia; rash; heart palpitation; blotting, western; mononuclear cell; drug mechanism; thrombosis; western blotting; safety; drug metabolism; phase 1 clinical trial; drug half life; urine retention; infusions, intravenous; oblimersen; proto-oncogene proteins c-bcl-2; concentration response; half-life; biological availability; oligonucleotides, antisense; peripheral lymphocyte; antisense oligonucleotide; transaminitis; nucleotide metabolism; genes, bcl-2; thionucleotides; transaminases; humans; human; priority journal; article
Journal Title: Clinical Cancer Research
Volume: 8
Issue: 3
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2002-03-01
Start Page: 679
End Page: 683
Language: English
PUBMED: 11895895
PROVIDER: scopus
DOI/URL:
Notes: Export Date: 14 November 2014 -- Source: Scopus
Citation Impact
MSK Authors
  1. William Ping-Yiu Tong
    158 Tong
  2. Neal Rosen
    425 Rosen
  3. Susan Slovin
    254 Slovin
  4. Michael Morris
    578 Morris
  5. William K Kelly
    115 Kelly
  6. Howard Scher
    1130 Scher
  7. Kathryn   Terry
    6 Terry