In:
Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 891-891
Abstract:
Tipifarnib (R115777, Zarnestra) is a methylquinolone analogue that is a potent inhibitor of farnesylation. The initial phase I study in leukemia by Karp and Lancet (Blood, 2001) showed clinical responses in 10/34 evaluable patients with AML on a 21 day schedule, with 600 mg bid identified as the MTD. Preclinical work shows that farnesyltransferase remains inhibited for seven days after tipifarnib, suggesting an alternate week dosing schedule. We report the results of a tipifarnib phase I dose escalation trial in AML on a week on week off schedule. Dose levels were 400, 600, 800, 1200, 1400, and 1600 mg BID on a standard 3+3 design. Eligibility was defined as relapsed or refractory AML after one to three prior induction regimens. A total of 37 patients were accrued, with 32 evaluable for toxicity. Median age at treatment is 62 (range 33–77), with 15 F, 22 M. RESULTS: The MTD on this schedule was 1200 mg B.I.D., with the major dose limiting toxicity determined by course one being creatinine elevation. At the 6 pts treated at the MTD there was one DLT (grade 3 creatinine), one grade 3 nausea (not a DLT), and grade 2 toxicities including liver enzyme abnormalities, nausea/vomiting, and rash. At dose level 1, metabolic acidosis and hepatic failure in a patient with progressive leukemia who had previous hepatic toxicity during chemotherapy was observed. Two patients treated at the MTD had a complete remission: a 69-yr old male who relapsed after 231 days, and a 66-yr old male who relapsed after 258 days, but who responded to re-treatment with tipifarnib and is disease-free 548 days (18 months) since enrolling in the study. At 1000mg BID dose, a 69-yr old woman with relapsed AML after autologous transplant had a CR after 2 cycles and went on receive a successful allogeneic transplant and is in remission 2yrs from her first cycle of tipifarnib. One patient with AML evolving out of CMMoL had disappearance of the AML blasts but persistence of the CMMoL after two cycles at the 800 mg bid level, and one patient at the 1400 dose had a platelet rise to 140 from a starting platelet count below 40 despite continued presence of blasts. Higher doses resulted in a higher incidence of dose limiting renal toxicity, fewer courses, and no complete remissions. Additional patients are accruing at the MTD to further understand the toxicities on this schedule. In AML patients, a two-fold increase in tipifarnib dosing can be tolerated on this dosing schedule with responses seen at the higher doses. A monotherapy phase 2 or tipifarnib combination study in AML using this schedule appears warranted.
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood.V110.11.891.891
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2007
detail.hit.zdb_id:
1468538-3
detail.hit.zdb_id:
80069-7
Permalink
