Phase I study of alternate-week administration of tipifarnib in patients with myelodysplastic syndrome.
OBJECTIVE
To determine the safety and describe the antitumor activity of tipifarnib in patients with myelodysplastic syndrome (MDS) using an alternate-week schedule.


METHODS
Patients with MDS were given tipifarnib, escalating from 100 mg orally twice daily until the maximum tolerated dose for 8 weeks followed by maintenance therapy (same dose/schedule) for patients with stable disease or better.


RESULTS
Sixty-three patients were treated. The most common toxicity was myelosuppression (60% of patients). Twenty percent of patients had no side effects. Nonhematologic toxicities included fatigue (20%), skin rash (9%), diarrhea (16%), increase in liver transaminases (14%) and bilirubin (11%), and nausea (11%). Dose-limiting toxicities of ataxia (n = 1), fatigue (n = 1), nausea (n = 1), and neutropenic fever (n = 2) occurred at tipifarnib doses above 1,200 mg/d. Sixteen of 61 (26%) evaluable patients responded (3 complete remissions and 13 hematologic improvements) with major platelet responses being most common (11 of 16 responders). There was no obvious dose-response relationship. Four of the 16 responders (25%; including a complete responder) were treated at the lowest dose level (100 mg twice daily). Only one responder had a Ras mutation. Giving tipifarnib resulted in potent inhibition of farnesyl transferase (usually more than 75%) in peripheral blood mononuclear cells regardless of dose. Partial farnesyl transferase inhibition persisted during the week off.


CONCLUSIONS
Alternate-week tipifarnib is active and well tolerated in patients with MDS at doses up to and including 600 mg orally twice daily. The biological activity of tipifarnib is not dependent on dose.
Kurzrock
Razelle
R
Phase I Program, University of Texas MD Anderson Cancer Center, Houston, TX 77230-1402, USA. rkurzroc@mdanderson.org
Kantarjian
Hagop M
HM
Blascovich
Michelle A
MA
Bucher
Cindy
C
Verstovsek
Srdan
S
Wright
John J
JJ
Pilat
Susan R
SR
Cortes
Jorge E
JE
Estey
Elihu H
EH
Giles
Francis J
FJ
Beran
Miloslav
M
Sebti
Said M
SM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D004334:Drug Administration Schedule; D051231:Farnesyltranstransferase / Q000276:immunology / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D015363:Quinolones / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use
D015363:Quinolones; D051231:Farnesyltranstransferase; C402769:tipifarnib