A phase II study of oral enzastaurin in patients with metastatic breast cancer previously treated with an anthracycline and a taxane containing regimen.
OBJECTIVE
Enzastaurin is a potent, serine-threonine kinase inhibitor which selectively targets PKCβ and PI3K/AKT signaling pathways to reduce cell proliferation, induce apoptosis, and inhibit angiogenesis. As PKCbeta and PI3K/AKT signaling are both involved in breast cancer pathogenesis, this phase II study evaluated the efficacy and toxicity of enzastaurin in previously treated patients with metastatic breast cancer (MBC).


METHODS
Eligible patients had histologically confirmed MBC with measurable disease, and must have received prior anthracycline and taxane chemotherapy, but not more than two prior regimens for MBC. Human epidermal growth factor 2 (HER2)-positive patients must have progressed on prior trastuzumab therapy. Enzastaurin, 1,125-mg loading dose on day 1 followed by 500 mg daily, was administered orally in 28-day cycles. Response was assessed every 2 cycles according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria.


RESULTS
Twenty-one patients enrolled between November 2006 and September 2007. Fourteen (66.7%) patients completed at least two cycles of therapy. No patients developed Grade 3/4 hematologic toxicity. Grade 3 nonhematologic toxicity was rare (<5%) and most commonly attributed to MBC progression. There were no objective responses and no patients with stable disease for >/=6 months. Median progression-free survival was 1.68 months (95%CI: 1.02, 1.74).


CONCLUSIONS
Enzastaurin monotherapy was well tolerated, but demonstrated no activity in patients with heavily pretreated MBC.
Mina
Lida
L
Indiana University Melvin and Bren Simon Cancer Center, 535 Barnhill Drive, Indianapolis, IN 46202, USA.
Krop
Ian
I
Zon
Robin T
RT
Isakoff
Steven J
SJ
Schneider
Charles J
CJ
Yu
Menggang
M
Johnson
Cindy
C
Vaughn
LaTrice G
LG
Wang
Yanping
Y
Hristova-Kazmierski
Maria
M
Shonukan
Oluwatoyin O
OO
Sledge
George W
GW
Miller
Kathy D
KD
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D018943:Anthracyclines / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D001952:Bridged-Ring Compounds / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D043823:Taxoids / Q000627:therapeutic use*; D016896:Treatment Outcome
D018943:Anthracyclines; D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D007211:Indoles; D043823:Taxoids; C080625:taxane; C504878:enzastaurin