Active oral regimen for elderly adults with newly diagnosed acute myelogenous leukemia: a preclinical and phase 1 trial of the farnesyltransferase inhibitor tipifarnib (R115777, Zarnestra) combined with etoposide.
The farnesyltransferase inhibitor tipifarnib exhibits modest activity against acute myelogenous leukemia. To build on these results, we examined the effect of combining tipifarnib with other agents. Tipifarnib inhibited signaling downstream of the farnesylated small G protein Rheb and synergistically enhanced etoposide-induced antiproliferative effects in lymphohematopoietic cell lines and acute myelogenous leukemia isolates. We subsequently conducted a phase 1 trial of tipifarnib plus etoposide in adults over 70 years of age who were not candidates for conventional therapy. A total of 84 patients (median age, 77 years) received 224 cycles of oral tipifarnib (300-600 mg twice daily for 14 or 21 days) plus oral etoposide (100-200 mg daily on days 1-3 and 8-10). Dose-limiting toxicities occurred with 21-day tipifarnib. Complete remissions were achieved in 16 of 54 (30%) receiving 14-day tipifarnib versus 5 of 30 (17%) receiving 21-day tipifarnib. Complete remissions occurred in 50% of two 14-day tipifarnib cohorts: 3A (tipifarnib 600, etoposide 100) and 8A (tipifarnib 400, etoposide 200). In vivo, tipifarnib plus etoposide decreased ribosomal S6 protein phosphorylation and increased histone H2AX phosphorylation and apoptosis. Tipifarnib plus etoposide is a promising orally bioavailable regimen that warrants further evaluation in elderly adults who are not candidates for conventional induction chemotherapy. These clinical studies are registered at www.clinicaltrials.gov as #NCT00112853.
Karp
Judith E
JE
Johns Hopkins Sidney Kimmel Cancer Center, Baltimore, MD 21231-1000, USA. jkarp2@jhmi.edu
Flatten
Karen
K
Feldman
Eric J
EJ
Greer
Jacqueline M
JM
Loegering
David A
DA
Ricklis
Rebecca M
RM
Morris
Lawrence E
LE
Ritchie
Ellen
E
Smith
B Douglas
BD
Ironside
Valerie
V
Talbott
Timothy
T
Roboz
Gail
G
Le
Son B
SB
Meng
Xue Wei
XW
Schneider
Paula A
PA
Dai
Nga T
NT
Adjei
Alex A
AA
Gore
Steven D
SD
Levis
Mark J
MJ
Wright
John J
JJ
Garrett-Mayer
Elizabeth
E
Kaufmann
Scott H
SH
D000284:Administration, Oral; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005047:Etoposide / Q000008:administration & dosage*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors; D018922:HL-60 Cells; D006801:Humans; D019169:Jurkat Cells; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology; D015363:Quinolones / Q000008:administration & dosage*; D014407:Tumor Cells, Cultured; D020298:U937 Cells
D004791:Enzyme Inhibitors; D015363:Quinolones; D005047:Etoposide; D051231:Farnesyltranstransferase; C402769:tipifarnib