A phase I trial of the dual farnesyltransferase and geranylgeranyltransferase inhibitor L-778,123 and radiotherapy for locally advanced pancreatic cancer.
OBJECTIVE
Preclinical and clinical studies have demonstrated that inhibition of prenylation can radiosensitize cell lines with activation of Ras and produce clinical response in patients with cancer. The aim of this study was to determine the maximally tolerated dose of the dual farnesyltransferase and geranylgeranyltransferase I inhibitor L-778,123 in combination with radiotherapy for patients with locally advanced pancreatic cancer.


METHODS
L-778,123 was given by continuous intravenous infusion with concomitant radiotherapy to 59.4 Gy in standard fractions. Two L-778,123 dose levels were tested: 280 mg/m2/day over weeks 1, 2, 4, and 5 for dose level 1; and 560 mg/m2/day over weeks 1, 2, 4, 5, and 7 for dose level 2.


RESULTS
There were no dose-limiting toxicities observed in the eight patients treated on dose level 1. Two of the four patients on dose level 2 experienced dose-limiting toxicities consisting of grade 3 diarrhea in one case and grade 3 gastrointestinal hemorrhage associated with grade 3 thrombocytopenia and neutropenia in the other case. Other common toxicities were mild neutropenia, dehydration, hyperglycemia, and nausea/vomiting. One patient on dose level 1 showed a partial response of 6 months in duration. Both reversible inhibition of HDJ2 farnesylation and radiosensitization of a study patient-derived cell line were demonstrated in the presence of L-778,123. K-RAS mutations were found in three of the four patients evaluated.


CONCLUSIONS
The combination of L-778,123 and radiotherapy at dose level 1 showed acceptable toxicity in patients with locally advanced pancreatic cancer. Radiosensitization of a patient-derived pancreatic cancer cell line was observed.
Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Neil E
NE
Martin
Thomas B
TB
Brunner
Krystina D
KD
Kiel
Thomas F
TF
DeLaney
William F
WF
Regine
Mohammed
M
Mohiuddin
Ernest F
EF
Rosato
Daniel G
DG
Haller
James P
JP
Stevenson
Debbie
D
Smith
Barnali
B
Pramanik
Joel
J
Tepper
Wesley K
WK
Tanaka
Briggs
B
Morrison
Paul
P
Deutsch
Anjali K
AK
Gupta
Ruth J
RJ
Muschel
W Gillies
WG
McKenna
Eric J
EJ
Bernhard
Stephen M
SM
Hahn
D000328:Adult; D000368:Aged; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D051231:Farnesyltranstransferase; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000633:toxicity*; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D016019:Survival Analysis; D013997:Time Factors
D007093:Imidazoles; C425231:L 778,123; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase