Annals of Oncology Advance Access published online on June 1, 2009
Annals of Oncology, doi:10.1093/annonc/mdp049
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Phase Ib safety and pharmacokinetic evaluation of daily and twice daily oral enzastaurin in combination with pemetrexed in advanced/metastatic cancer
,*
1 I. Medical Department, General Hospital, St Georg, Hamburg, Germany
2 Early Phase Clinical Oncology Development, Eli Lilly and Company, Indianapolis, IN, USA
3 Medical Clinic 5, Oncology and Hematology, Clinic Nürnberg Nord, Nürnberg
4 I. Medical Department, General Hospital, Hamburg, Germany
5 Department of Medical Oncology, VU Medical Center, Amsterdam, Netherlands
* Correspondence to: Dr G. Giaccone, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1906, USA. Tel: +1-301-402-3415; Fax: +1-301-402-0172; E-mail: giacconeg{at}mail.nih.gov
Background: This phase Ib study evaluated the safety, pharmacokinetics, and activity of enzastaurin either 500 mg once daily (QD) or 250 mg twice daily (b.i.d.) in combination with pemetrexed.
Patients and methods: Pemetrexed 500 mg/m2 with folic acid and vitamin B12 was given on day 1 every 21 days with enzastaurin 500 mg orally QD starting on day 5 of cycle 1 after a loading dose of 400 mg thrice daily on day 4. To evaluate whether a b.i.d. regimen results in higher enzastaurin exposures, the study was amended. After amendment, in cycle 1, patients received 500 mg enzastaurin QD on days 1–15 without initial loading dose and 250 mg b.i.d. on days 16–30; in subsequent cycles, patients received pemetrexed on day 1 every 21 days with enzastaurin b.i.d.
Results: Sixty-eight patients (42 preamendment and 26 postamendment) were assessed. Pemetrexed toxicity and pharmacokinetics did not appear to be altered by enzastaurin. Enzastaurin average steady-state plasma concentration (Cav,ss) decreased by 
25% in the presence of pemetrexed. Enzastaurin Cav,ss were 40% higher in the b.i.d. versus QD regimen. Three patients (4.4%) with thyroid cancer of follicular/papillary type had partial response as defined by RECIST.
Conclusions: Pemetrexed plus enzastaurin is well tolerated with preliminary evidence of anticancer activity, particularly in thyroid cancer.
enzastaurin, pemetrexed, pharmacokinetics, phase I, safety
Present address: Global Brand Development Oncology, Eli Lilly and Company, Indianapolis, IN, USA.
Present address: Center for Cancer Research, Medical Oncology and Affiliates Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Received for publication September 22, 2008. Revision received December 23, 2008. Accepted for publication February 3, 2009.