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

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 7 days with bolus A (50 mg/m2) and T (75 mg/m2) administered on either day 3 or 6 of therapy with G3139. Cycles were repeated every 21 days x 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.

• Authors: 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 23 Pg. 7909-16 (Dec 01 2008) ISSN: 1078-0432 [Print] United States
• PMID: 19047121 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Proto-Oncogene Proteins c-bcl-2
• Taxoids
• Thionucleotides
• Docetaxel
• Doxorubicin
• oblimersen

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (pharmacokinetics, therapeutic use)
• Breast Neoplasms (drug therapy)
• Docetaxel
• Doxorubicin (administration & dosage, adverse effects)
• Female
• Humans
• Middle Aged
• Proto-Oncogene Proteins c-bcl-2 (biosynthesis, drug effects)
• Reverse Transcriptase Polymerase Chain Reaction
• Taxoids (administration & dosage, adverse effects)
• Thionucleotides (administration & dosage, adverse effects, pharmacokinetics)