A phase I safety, tolerability, and pharmacokinetic study of enzastaurin combined with capecitabine in patients with advanced solid tumors.
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.
Camidge
D Ross
DR
Division of Medical Oncology, University of Colorado Cancer Center, Aurora, Colorado 80045, USA. ross.camidge@uchsc.edu
Gail Eckhardt
S
S
Gore
Lia
L
O'Bryant
Cindy L
CL
Leong
Stephen
S
Basche
Michelle
M
Holden
Scott N
SN
Musib
Luna
L
Baldwin
John
J
Darstein
Christelle
C
Thornton
Donald
D
Finn
Richard S
RS
Britten
Carolyn D
CD
D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D000069287:Capecitabine; D015331:Cohort Studies; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D005260:Female; D005467:Floxuridine / Q000097:blood; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood; D005500:Follow-Up Studies; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D064546:Protein Kinase C beta
D000903:Antibiotics, Antineoplastic; D007211:Indoles; D005467:Floxuridine; D003841:Deoxycytidine; D000069287:Capecitabine; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D005472:Fluorouracil; C504878:enzastaurin; C025034:doxifluridine