Phase I pharmacokinetic and pharmacodynamic study of the oral protein kinase C beta-inhibitor enzastaurin in combination with gemcitabine and cisplatin in patients with advanced cancer.
OBJECTIVE
Enzastaurin targets the protein kinase C and phosphatidylinositol 3-kinase/AKT pathways to reduce tumor angiogenesis and cell proliferation and to induce cell death. A phase I trial was conducted to evaluate the feasibility of combining enzastaurin with gemcitabine and cisplatin.


METHODS
Patients with advanced cancer received a 14-day lead-in treatment with oral enzastaurin followed by subsequent 21-day cycles of daily enzastaurin, gemcitabine on days 1 and 8, and cisplatin on day 1. Enzastaurin doses were escalated between 350 mg once daily to 500 mg twice daily, whereas gemcitabine doses were either 1,000 or 1,250 mg/m(2) and cisplatin doses were either 60 or 75 mg/m(2). Circulating endothelial cell numbers and CD146 and CD133 mRNA expression were evaluated as pharmacodynamic markers.


RESULTS
Thirty-three patients (median age, 58 years) were enrolled in seven dose levels. The maximum tolerated dose was not identified. Two dose-limiting toxicities (grade 2 QT interval corrected for heart rate prolongation and grade 3 fatigue) were reported. Other toxicities included grade 3/4 neutropenia (3 of 6 patients), thrombocytopenia (1 of 6 patients), grade 3 leukopenia (2 patients), and fatigue (5 patients). Enzastaurin twice daily (> or =250 mg) resulted in more discontinuations and low-grade toxicities. In the combination, enzastaurin exposures decreased slightly but remained above the target of 1,400 nmol/L, whereas gemcitabine/cisplatin exposures were unaltered. Three patients (9.1%) had partial responses and 13 (39.4%) had stable disease. Measurement of circulating endothelial cell numbers and CD146 and CD133 mRNA expression did not contribute to decision-making on dose escalation.


CONCLUSIONS
Recommended phase II dose is 500 mg enzastaurin once daily, 1,250 mg/m(2) gemcitabine, and 75 mg/m(2) cisplatin. This regimen is well tolerated with no significant alterations in the pharmacokinetic variables of any drug.
Rademaker-Lakhai
Jeany M
JM
Department of Medical Oncology, Antoni van Leeuwenhoek Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands. jeanyrademaker@quicknet.nl
Beerepoot
Laurens V
LV
Mehra
Niven
N
Radema
Sandra A
SA
van Maanen
Rianne
R
Vermaat
Joost S
JS
Witteveen
Els O
EO
Visseren-Grul
Carla M
CM
Musib
Luna
L
Enas
Nathan
N
van Hal
Gertjan
G
Beijnen
Jos H
JH
Schellens
Jan H M
JH
Voest
Emile E
EE
D000071916:AC133 Antigen; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000235:genetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051929:CD146 Antigen / Q000235:genetics; D002945:Cisplatin / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004730:Endothelium, Vascular / Q000473:pathology; D005260:Female; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000097:blood / Q000188:drug therapy / Q000517:prevention & control; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D010455:Peptides / Q000235:genetics; D011379:Prognosis; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D064546:Protein Kinase C beta; D012333:RNA, Messenger / Q000378:metabolism; D015996:Survival Rate; D000093542:Gemcitabine
D000071916:AC133 Antigen; D015703:Antigens, CD; D051929:CD146 Antigen; D006023:Glycoproteins; D007211:Indoles; C000606023:PROM1 protein, human; D010455:Peptides; D012333:RNA, Messenger; D003841:Deoxycytidine; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D002945:Cisplatin; C504878:enzastaurin; D000093542:Gemcitabine