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

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/m(2)/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.