A phase II study of farnesyl transferase inhibitor R115777 in pancreatic cancer: a Southwest oncology group (SWOG 9924) study.
Ninety per cent of pancreatic adenocarcinomas (PC) contain mutations of the K-Ras proto-oncogene resulting in constitutively activated Ras protein. A critical step in Ras activation is farnesylation of Ras protein. Farnesyl transferase inhibitors are compounds that inhibit farnesylation. We report the results of a phase II trial of R115777, an oral farnesyl transferase inhibitor, in patients with surgically incurable locally advanced or metastatic PC. Between 6/1/2000 and 11/20/2001, 58 cases were accrued, 53 of whom were eligible and analyzable. Patients were required to have a performance status (PS) 0 to 1, be able to take oral medications, and to have adequate renal, hepatic, and hematologic functions. Fifty-five percent were male. Median age was 64.7 years (38.9 to 80.6), and patients had no previous systemic therapy for advanced PC. Treatment consisted of R115777 300 mg po bid given for 3 out of every 4 weeks. Toxicities were as follows: Grade 3 in 19/53 (36%), grade 4 in 53 (173%), and grade 5 in 53 (8%). Most frequent toxicities were: anemia 35/53 (66%), fatigue and malaise 33/53 (62%), nausea 31/53 (58%). Grade 5 toxicities included: thromboembolism 1, infection 2, other 1. Median survival was 2.6 months (mo) (95% CI 2.1-3.6), 6-mo survival is 19% (95% CI, 8-29%), median time to treatment failure was 1.4 mo (95% GI 1.1-1.6). R115777 is ineffective as monotherapy in advanced pancreatic cancer.
Macdonald
John S
JS
St. Vincent's Comprehensive Cancer Center, 325 W 15th Street, New York, NY 10011, USA. jmacdona@salick.com
McCoy
Sheryl
S
Whitehead
Robert P
RP
Iqbal
Syma
S
Wade
James L
JL
Giguere
Jeffrey K
JK
Abbruzzese
James L
JL
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000139:chemically induced; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000401:mortality; D000090063:Proto-Oncogene Mas; D015363:Quinolones / Q000009:adverse effects / Q000627:therapeutic use*; D015996:Survival Rate; D016896:Treatment Outcome
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D015363:Quinolones; D051231:Farnesyltranstransferase; C402769:tipifarnib