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

Charles M. Rudin, Mark Kozloff, Philip C. Hoffman, Martin J. Edelman, Robyn Karnauskas, Ronald Tomek, Livia Szeto, Everett E. Vokes

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1110-1117
Number of pages8
JournalJournal of Clinical Oncology
Volume22
Issue number6
DOIs
StatePublished - 2004
Externally publishedYes

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Antisense Oligonucleotides
Carboplatin
Small Cell Lung Carcinoma
Etoposide
Area Under Curve
Blood Cells
Phosphorothioate Oligonucleotides
oblimersen
Neutropenia
Pharmacokinetics
Drug Therapy
Messenger RNA

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Phase I study of G3139, a bcl-2 antisense oligonucleotide, combined with carboplatin and etoposide in patients with small-cell lung cancer. / Rudin, Charles M.; Kozloff, Mark; Hoffman, Philip C.; Edelman, Martin J.; Karnauskas, Robyn; Tomek, Ronald; Szeto, Livia; Vokes, Everett E.

In: Journal of Clinical Oncology, Vol. 22, No. 6, 2004, p. 1110-1117.

Research output: Contribution to journalArticle

Rudin, CM, Kozloff, M, Hoffman, PC, Edelman, MJ, Karnauskas, R, Tomek, R, Szeto, L & Vokes, EE 2004, 'Phase I study of G3139, a bcl-2 antisense oligonucleotide, combined with carboplatin and etoposide in patients with small-cell lung cancer', Journal of Clinical Oncology, vol. 22, no. 6, pp. 1110-1117. https://doi.org/10.1200/JCO.2004.10.148
Rudin, Charles M. ; Kozloff, Mark ; Hoffman, Philip C. ; Edelman, Martin J. ; Karnauskas, Robyn ; Tomek, Ronald ; Szeto, Livia ; Vokes, Everett E. / Phase I study of G3139, a bcl-2 antisense oligonucleotide, combined with carboplatin and etoposide in patients with small-cell lung cancer. In: Journal of Clinical Oncology. 2004 ; Vol. 22, No. 6. pp. 1110-1117.
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abstract = "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.",
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T1 - Phase I study of G3139, a bcl-2 antisense oligonucleotide, combined with carboplatin and etoposide in patients with small-cell lung cancer

AU - Rudin, Charles M.

AU - Kozloff, Mark

AU - Hoffman, Philip C.

AU - Edelman, Martin J.

AU - Karnauskas, Robyn

AU - Tomek, Ronald

AU - Szeto, Livia

AU - Vokes, Everett E.

PY - 2004

Y1 - 2004

N2 - 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.

AB - 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.

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