Phase I study of G3139, a bcl-2 antisense oligonucleotide, combined with carboplatin and etoposide in patients with small-cell lung cancer

J Clin Oncol. 2004 Mar 15;22(6):1110-7. doi: 10.1200/JCO.2004.10.148.


Purpose: Bcl-2 is expressed in the majority of cases of small cell lung cancer (SCLC) and may contribute to chemotherapeutic resistance. Bcl-2 suppression by G3139 (oblimersen sodium), a phosphorothioate oligonucleotide complementary to the bcl-2 mRNA, has the potential to enhance the antitumor efficacy of standard cytotoxic chemotherapy. A dose-finding study was performed evaluating the combination of G3139, carboplatin, and etoposide in patients with previously untreated extensive stage SCLC.

Patients and methods: Sixteen patients were treated in three consecutive cohorts. Cohort 1 (n=5) received G3139 5 mg/kg/d on days 1 to 8 of a 21 day cycle, with carboplatin area under the curve (AUC)=6 on day 6, and etoposide 80 mg/m2/d on days 6 to 8. In cohort 2 (n=4), carboplatin dose was reduced to AUC=5. In cohort 3 (n=7), G3139 dose was escalated to 7 mg/kg/d. G3139 plasma concentrations and Bcl-2 protein levels in peripheral blood mononuclear cells were evaluated.

Results: Two of three assessable patients in cohort 1 experienced cycle 1 dose-limiting toxicity (grade 4 neutropenia). No cycle 1 dose-limited toxicity was observed in cohorts 2 or 3. Of 14 patients assessable for response, partial response was documented in 12 patients (86%), and stable disease in two. Median time to progression was 5.9 months. Carboplatin and etoposide administration did not appear to alter G3139 pharmacokinetics. No evidence of Bcl-2 suppression in peripheral blood mononuclear cells was observed.

Conclusion: The combination of G3139, carboplatin, and etoposide is well tolerated and results in an encouraging response rate and time to progression in patients with extensive stage SCLC.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Carboplatin / administration & dosage
  • Carboplatin / pharmacokinetics
  • Carcinoma, Small Cell / drug therapy*
  • Carcinoma, Small Cell / mortality
  • Disease-Free Survival
  • Dose-Response Relationship, Drug
  • Etoposide / administration & dosage
  • Etoposide / pharmacokinetics
  • Female
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / mortality
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Oligonucleotides, Antisense / administration & dosage
  • Oligonucleotides, Antisense / pharmacokinetics
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Survival Rate
  • Thionucleotides / administration & dosage*
  • Thionucleotides / pharmacokinetics
  • United States / epidemiology


  • Antineoplastic Agents
  • Oligonucleotides, Antisense
  • Proto-Oncogene Proteins c-bcl-2
  • Thionucleotides
  • Etoposide
  • oblimersen
  • Carboplatin