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Phase I/II Study of G3139 (Bcl-2 Antisense Oligonucleotide) in Combination with Doxorubicin and Docetaxel in Breast Cancer

Authors' Affiliations: ¹ Departments of Breast Medical Oncology, Pathology, Surgical Oncology, Radiation Oncology and Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas and ² Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland

Requests for reprints: Francisco J. Esteva, Department of Breast Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Unit 1354, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-2817; Fax: 713-563-0739; E-mail: fjesteva{at}mdanderson.org.

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.