Dose-ranging pharmacodynamic study of tipifarnib (R115777) in patients with relapsed and refractory hematologic malignancies.
OBJECTIVE
Tipifarnib, an orally bioavailable inhibitor of farnesyl transferase, has activity in hematologic malignancies, but the dose required to achieve the proposed biologic end point, inhibition of farnesylation, is unknown.


METHODS
The impact on post-translational farnesylation was assessed in 42 patients with refractory hematologic malignancies and bone marrow involvement. Tipifarnib was taken orally for 21 days of a 28-day cycle. For cycle 1, patients were randomly assigned to one of four dose levels: 100 mg bid, 200 mg bid, 300 mg bid, and 600 mg bid. In cycle 1, peripheral blood and bone marrow mononuclear cells were analyzed for inhibition of HDJ2 prenylation by Western blot analysis at baseline and on day 21.


RESULTS
Twenty-three patients were assessable for analysis of HDJ2 prenylation before and after therapy. Inhibition of farnesylation was noted at all dose levels, although the highest level of inhibition was noted at the 300-mg-bid dose. The inhibition of farnesylation in the peripheral blood correlated with the inhibition in the bone marrow (r = 0.62). Of the 26 patients assessable for clinical activity after cycle 1, three patients had a significant decrease in total blasts count (acute myeloid leukemia in two patients, and chronic myelogenous leukemia in one patient). The inhibition of farnesylation was greater in the three responders than the nonresponders (P = .03).


CONCLUSIONS
Farnesylation as measured by HDJ2 analysis was inhibited at all dose levels administered. Clinical activity may correlate with the degree of farnesylation inhibition, rather than dose of tipifarnib, and escalation beyond 300 mg bid might not result in additional clinical activity.
Zimmerman
Todd M
TM
Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA. tzimmerm@medicine.bsd.uchicago.edu
Harlin
Helena
H
Odenike
Olatoyosi M
OM
Berk
Seth
S
Sprague
Evie
E
Karrison
Theodore
T
Stock
Wendy
W
Larson
Richard A
RA
Ratain
Mark J
MJ
Gajewski
Thomas F
TF
D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D001682:Biological Availability; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D019337:Hematologic Neoplasms / Q000175:diagnosis* / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D015363:Quinolones / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D018570:Risk Assessment; D016879:Salvage Therapy; D018709:Statistics, Nonparametric; D016019:Survival Analysis; D016896:Treatment Outcome
D015363:Quinolones; C402769:tipifarnib