Phase II and pharmacodynamic study of the farnesyltransferase inhibitor R115777 as initial therapy in patients with metastatic pancreatic adenocarcinoma.
OBJECTIVE
R115777 is a selective nonpeptidomimetic inhibitor of farnesyltransferase (FTase), one of several enzymes responsible for posttranslational modification that is required for the function of p21(ras) and other proteins. Given that RAS mutations are nearly universal in pancreatic cancer and R115777 demonstrated preclinical activity against pancreatic cell lines and xenografts, this phase II study was undertaken to determine its clinical activity and effect on target proteins in patients with measurable metastatic pancreatic adenocarcinoma.


METHODS
Twenty patients who had not received prior therapy for metastatic disease were treated with 300 mg of R115777 orally every 12 hours for 21 of 28 days. Inhibition of FTase activity in peripheral-blood mononuclear cells was measured using a lamin B C-terminus peptide as substrate. Western blot analysis was performed to monitor farnesylation status of the chaperone protein HDJ-2.


RESULTS
No objective responses were seen. Median time to progression was 4.9 weeks, and median survival time was 19.7 weeks. The estimated 6-month survival rate was 25%, with no patients progression-free at 6 months. Grade 3/4 toxicities were liver enzyme elevation, anemia, neutropenia, thrombocytopenia, fatigue, nausea/vomiting, rash, and anorexia. FTase activity (mean +/- SD) decreased by 49.8% +/- 9.8% 4 hours after treatment on day 1 and 36.1% +/- 24.8% before treatment on day 15. HDJ-2 farnesylation (mean +/- SD) decreased by 33.4% +/- 19.8% on day 15.


CONCLUSIONS
Although treatment with R115777 resulted in partial inhibition of FTase activity in mononuclear cells, it did not exhibit single-agent antitumor activity in patients with previously untreated metastatic pancreatic cancer.
Cohen
Steven J
SJ
Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Ho
Linus
L
Ranganathan
Sulabha
S
Abbruzzese
James L
JL
Alpaugh
R Katherine
RK
Beard
Mary
M
Lewis
Nancy L
NL
McLaughlin
Susan
S
Rogatko
André
A
Perez-Ruixo
Juan J
JJ
Thistle
Amanda M
AM
Verhaeghe
Tom
T
Wang
Hao
H
Weiner
Louis M
LM
Wright
John J
JJ
Hudes
Gary R
GR
Meropol
Neal J
NJ
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality; D000328:Adult; D000368:Aged; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D002352:Carrier Proteins / Q000378:metabolism; D018450:Disease Progression; D051231:Farnesyltranstransferase; D005260:Female; D050956:HSP40 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000401:mortality; D015363:Quinolones / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D002352:Carrier Proteins; C107481:DNAJA1 protein, human; D050956:HSP40 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D015363:Quinolones; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; C402769:tipifarnib