A phase I trial of CEP-701 + gemcitabine in patients with advanced adenocarcinoma of the pancreas.
BACKGROUND
Current standard therapy for advanced pancreas cancer includes the use of gemcitabine or a gemcitabine-based chemotherapy regimen. Based on pre-clinical data, the combination of CEP-701, an inhibitor of tyrosine kinases including Flt-3, TRK-A/B and JCK-2, with gemcitabine appeared promising.


METHODS
Two clinical sites were chosen for this phase I trial, one scheduled to start gemcitabine prior to CEP-701 and one scheduled to start CEP-701 prior to gemcitabine. Gemcitabine was given at a dose of 1,000 mg/m2 over 30 min each week for 3 weeks in a row followed by 1 week off. CEP 701 was taken orally twice daily at doses ranging from 20 mg bid to 40 mg bid. Pharmacokinetics of both drugs were determined to assess for any drug-drug interactions.


RESULTS
Eighteen patients were enrolled and 17 received at least one dose of study drug. Nine patients experienced serious adverse events, but only one patient's toxicity was attributed as possibly secondary to study drug. No radiologic responses were seen. No significant pharmacokinetic interactions were observed between gemcitabine and CEP 701. The combination was well-tolerated, and the MTD was not reached in this study.


CONCLUSIONS
No unexpected toxicities were seen for this combination. Although too few patients were enrolled to fully evaluate efficacy, there was not significant evidence for pursuing this combination further in pancreas cancer. The maximum tolerated dose of the combination was not determined secondary to the early termination of the study.
Chan
Emily
E
Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN, USA. Emily.chan@vanderbilt.edu
Mulkerin
Daniel
D
Rothenberg
Mace
M
Holen
Kyle D
KD
Lockhart
A Craig
AC
Thomas
James
J
Berlin
Jordan
J
D000230:Adenocarcinoma / Q000188:drug therapy*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002227:Carbazoles / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D005663:Furans; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D000093542:Gemcitabine
D002227:Carbazoles; D005663:Furans; D003841:Deoxycytidine; C119379:lestaurtinib; D000093542:Gemcitabine