Phase I/II study of G3139 (Bcl-2 antisense oligonucleotide) in combination with doxorubicin and docetaxel in breast cancer.
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.
Moulder
Stacy L
SL
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.
Symmans
W Fraser
WF
Booser
Daniel J
DJ
Madden
Timothy L
TL
Lipsanen
Cindy
C
Yuan
Linda
L
Brewster
Abenaa M
AM
Cristofanilli
Massimo
M
Hunt
Kelly K
KK
Buchholz
Thomas A
TA
Zwiebel
James
J
Valero
Vicente
V
Hortobagyi
Gabriel N
GN
Esteva
Francisco J
FJ
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
D019253:Proto-Oncogene Proteins c-bcl-2; D043823:Taxoids; D013873:Thionucleotides; D000077143:Docetaxel; D004317:Doxorubicin; C408162:oblimersen