A phase II study of oral enzastaurin in patients with metastatic breast cancer previously treated with an anthracycline and a taxane containing regimen
Purpose: 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 PKCβ 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). Patients and 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.
KeywordsEnzastaurin Metastatic breast cancer Phase II
This trial was supported by Eli Lilly and Company, Indianapolis, IN. The authors thank Luna Musib and John Gill for their editorial support.
- 5.Gliki G, Wheeler-Jones C, Zachary I (2002) Vascular endothelial growth factor induces protein kinase C (PKC)-dependent Akt/PKB activation and phosphatidylinositol 3′-kinase-mediated PKC δ phosphorylation: role of PKC in angiogenesis. Cell Biol Int 26:751–759 doi: 10.1016/S1065-6995(02)90926-1 CrossRefPubMedGoogle Scholar
- 8.Hanauske AR, Oberschmidt O, Hanauske-Abel H et al (2007) Antitumor activity of enzastaurin (LY317615.HCl) against human cancer cell lines and freshly explanted tumors investigated in in vitro soft-agar cloning experiments. Invest New Drugs 25:205–210 doi: 10.1007/s10637-007-9038-7 CrossRefPubMedGoogle Scholar
- 11.Graff JR, McNulty AM, Hanna KR et al (2005) The protein kinase Cβ-selective inhibitor, Enzastaurin (LY317615.HCl), suppresses signaling through the AKT pathway, induces apoptosis, and suppresses growth of human colon cancer and glioblastoma xenografts. Cancer Res 65:7462–7469 doi: 10.1158/0008-5472.CAN-05-0071 CrossRefPubMedGoogle Scholar
- 14.Leong S, Camidge R, Eckhardt G et al (2006) A phase I dose-escalation and pharmacokinetic study of enzastaurin combined with capecitabine in patients with advanced cancer. ASCO 24S:2048Google Scholar
- 18.National Cancer Institute (2006) Common terminology criteria for adverse events, version 3.0. Available at http://ctep.cancer.gov/forms/CTCAEv3.pdf
- 21.Rademaker-Lakhai J, Beerepoot L, Mehra N et al (2007) Phase I pharmacokinetic and pharmacodynamic study of the oral protein kinase C β-inhibitor enzastaurin in combination with gemcitabine and cisplatin in advanced cancer. Clin Cancer Res 13:4474–4481 doi: 10.1158/1078-0432.CCR-06-2912 CrossRefPubMedGoogle Scholar
- 22.Cobleigh MA, Vogel CL, Tripathy D et al (1999) Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 17:2639–2648PubMedGoogle Scholar