Phase I/II study of G3139 (Bcl-2 antisense oligonucleotide) in combination with doxorubicin and docetaxel in breast cancer

Stacy L. Moulder, W. Fraser Symmans, Daniel J. Booser, Timothy L. Madden, Cindy Lipsanen, Linda Yuan, Abenaa M. Brewster, Massimo Cristofanilli, Kelly K. Hunt, Thomas A. Buchholz, James Zwiebel, Vicente Valero, Gabriel N. Hortobagyi, Francisco J. Esteva

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

Purpose:Preclinical data showed enhancement of breast cancer cell death when G3139 was combined with anthracyclines and taxanes. We evaluated the efficacy and safety of a Bcl-2 antisense oligonucleotide, G3139, in combination with doxorubicin (A) and docetaxel (T) in patients with locally advanced breast cancer (LABC). Experimental Design:Following a brief phase I to determine the phase II dose, patients with locally advanced breast cancer received G3139 administered by continuous i.v. infusion for 5 to 7days with bolus A(50 mg/m 2) andT (75 mg/m 2) administered on either day 3 or 6 of therapy with G3139. Cycles were repeated every 21 days ×6 in the neoadjuvant setting. Serial plasma samples were obtained for pharmacokinetic analysis. Tissue samples were obtained before and after therapy for pharmacodynamic analysis of Bcl-2 expression. Results:Thirty patients (median age, 49 years;range, 24-71 years) received 160 cycles. During the phase I portion of the trial, the dose of G3139 was escalated from 3 to 7 mg/kg/d (i.v. for 5 days) in combination with AT During the phase II portion of the trial, several doses and schedules of G3139 were evaluated. There were no pathologic complete responses. Pharmacodynamic studies showed limited Bcl-2 down-regulation in the primary tumors. Conclusions:G3139 in combination with doxorubicin and docetaxel is well tolerated. No pathologic complete response was seen and pharmacodynamic studies showed very little down-regulation of Bcl-2 in primary tumors, perhaps related to issues with insufficient drug delivery to the intact tumor.

Original languageEnglish (US)
Pages (from-to)7909-7916
Number of pages8
JournalClinical Cancer Research
Volume14
Issue number23
DOIs
StatePublished - Dec 1 2008

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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