Enzastaurin, an oral inhibitor of
protein kinase Cbeta, affects signal transduction associated with angiogenesis, proliferation, and survival.
Capecitabine is converted to 5-fluoruracil by
thymidine phosphorylase, a putative
angiogenic factor. The all-oral combination of the two drugs offers the potential for targeting angiogenesis in
capecitabine-sensitive
tumors with nonoverlapping toxicities. Patients with advanced
cancer initially received single-agent
enzastaurin to achieve steady-state concentrations (cycle 1). In subsequent 21-day cycles,
enzastaurin was given orally, once daily, on days 1-21 and
capecitabine orally, twice daily (b.i.d.), on days 1-14 in three dose-level cohorts. Three dose-escalation cohorts were studied: cohort 1 (n=8), 350 mg of
enzastaurin +capecitabine (750 mg/m2 b.i.d.); cohort 2 (n=7),
enzastaurin (350 mg)+
capecitabine (1000 mg/m2 b.i.d.); cohort 3 (n=12), 525-mg capsules or 500-mg enzastaurin+capecitabine (1000 mg/m2 b.i.d.). Further dose escalation was not pursued because of emerging data that
enzastaurin systemic exposure did not increase at doses above 525 mg. Although a traditional toxicity-based maximum tolerated dose was not achieved, the highest dosing cohort represented a biologically relevant dose of
enzastaurin, on the basis of preclinical data and correlative pharmacodynamic
biomarker assays of
protein kinase Cbeta inhibition in peripheral blood mononucleocytes, in combination with a standard dose of
capecitabine. For the 500/525-mg dose, ratios of total
enzastaurin analyte geometric means (i.e.
enzastaurin alone versus
enzastaurin with
capecitabine) reflected a trend toward decreased
enzastaurin exposure, but did not reach statistical significance. The pharmacokinetic parameters of
capecitabine with
enzastaurin were similar to those previously reported for single-agent
capecitabine. The regimen was well tolerated, without any consistent pattern of drug-related grade 3 or grade 4 toxicities being observed. Although no objective
tumor responses were documented, five patients maintained stable disease for >or=6 months (range: 6-9.7 months). The recommended phase II dose of this combination, based on the results of this study, is
enzastaurin at a daily dose of 500 mg (
tablet formulation) and
capecitabine (1000 mg/m2, b.i.d.) on days 1-14 every 21 days. Further disease-directed studies are warranted, such as in
malignancies in the treatment of which both
capecitabine and inhibitors of angiogenesis have previously been benchmarked as being effective.