A phase 1-2 study of a farnesyltransferase inhibitor, tipifarnib, combined with idarubicin and cytarabine for patients with newly diagnosed acute myeloid leukemia and high-risk myelodysplastic syndrome.
BACKGROUND
The authors conducted a phase 1/2 study of tipifarnib in combination with idarubicin and cytarabine (IA) in 95 patients with previously untreated acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome.


METHODS
Induction consisted of idarubicin 12 mg/m(2) a day on days 1-3, cytarabine 1.5 g/m(2) intravenously continuously daily on days 1-4 (days 1-3 if age ≥60 years), and tipifarnib, with the first cohort (n = 6) receiving 200 mg orally twice a day and all others receiving 300 mg twice a day for 21 days every 28 days. Consolidation consisted of 5 courses of idarubicin 8 mg/m(2) a day on days 1-2, cytarabine 0.75 g/m(2) a day on days 1-3, and tipifarnib 300 mg twice a day for 14 days every 4-6 weeks. Maintenance with tipifarnib 300 mg twice a day for 21 days every 4-6 weeks was continued for 6 months.


RESULTS
With a median follow-up of 33 months, 61 patients achieved complete remission (CR) (64%), and 9 achieved complete remission with incomplete platelet recovery (CRp) (9%). The median duration of CR was not reached. Median overall survival was 17 months. The most common grade 3 adverse events were gastrointestinal toxicities, liver dysfunction, and skin rash. Compared with historical IA, IA and tipifarnib showed a better CR duration (P = .04) and a trend toward a higher CR rate in patients with chromosome 5/7 abnormalities.


CONCLUSIONS
The combination of IA and tipifarnib is safe and active. Further studies exploring different dosages and schedules are warranted, particularly in patients with poor-risk AML.
Department of Leukemia, The University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Elias
E
Jabbour
Hagop
H
Kantarjian
Farhad
F
Ravandi
Guillermo
G
Garcia-Manero
Zeev
Z
Estrov
Srdan
S
Verstovsek
Susan
S
O'Brien
Stefan
S
Faderl
Deborah A
DA
Thomas
John J
JJ
Wright
Jorge
J
Cortes
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003561:Cytarabine / Q000008:administration & dosage* / Q000009:adverse effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors; D006801:Humans; D015255:Idarubicin / Q000008:administration & dosage* / Q000009:adverse effects; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000453:epidemiology / Q000473:pathology; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D015363:Quinolones / Q000008:administration & dosage* / Q000009:adverse effects; D012074:Remission Induction; D012306:Risk; D055815:Young Adult
D004791:Enzyme Inhibitors; D015363:Quinolones; D003561:Cytarabine; D051231:Farnesyltranstransferase; C402769:tipifarnib; D015255:Idarubicin