title: Phase I/II study of G3139 (Bcl-2 antisense oligonucleotide) in combination with doxorubicin and docetaxel in breast cancer.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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.affiliation: Department of Breast Medical Oncology, Pathology, Surgical Oncology, Radiation Oncology and Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Stacy L
authors.initials: SL
authors.lastname: Moulder
authors.forename: W Fraser
authors.initials: WF
authors.lastname: Symmans
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Booser
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Madden
authors.forename: Cindy
authors.initials: C
authors.lastname: Lipsanen
authors.forename: Linda
authors.initials: L
authors.lastname: Yuan
authors.forename: Abenaa M
authors.initials: AM
authors.lastname: Brewster
authors.forename: Massimo
authors.initials: M
authors.lastname: Cristofanilli
authors.forename: Kelly K
authors.initials: KK
authors.lastname: Hunt
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Buchholz
authors.forename: James
authors.initials: J
authors.lastname: Zwiebel
authors.forename: Vicente
authors.initials: V
authors.lastname: Valero
authors.forename: Gabriel N
authors.initials: GN
authors.lastname: Hortobagyi
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Esteva
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D000077143:Docetaxel; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006801:Humans; D008875:Middle Aged; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects; D013873:Thionucleotides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D043823:Taxoids; D013873:Thionucleotides; D000077143:Docetaxel; D004317:Doxorubicin; C408162:oblimersen