A Phase I Study of the Farnesyltransferase Inhibitor Tipifarnib in a Week- on Week-Off Dose Schedule in Acute Myelogenous Leukemia.

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 30 patients have been accrued. with 27 patients evaluable for toxicity. Median age is 64.5 (range 33–75). Grade 3 toxicities were seen at dose levels 1 (400 mg bid)- metabolic acidosis and hepatic failure in a patient with progressive leukemia who had previous hepatic toxicity during chemotherapy, and level 5 (1200 mg bid)- grade 3 creatinine elevation. Other grade 1 and 2 toxicities included fatigue, nausea, anorexia, elevated liver enzymes, increased bilirubin, and renal insufficiency. The maximum target treatment dose, 1600 mg PO bid was attained. There were 3 complete responses (CR) out of 9 patients treated at the 1000–1200 mg bid dose level- after cycle 1 in a 47 year old woman with relapsed AML after autologous transplant, with a 10 month continuing remission as of 8/06 (she underwent successful allogeneic transplant); after 2 cycles in a 69 year old man with relapsed AML, who relapsed after 5 months, (with response after retreatment with tipifarnib), and in a 67 year old man with relapsed AML who achieved PR after one cycle and CR after five cycles. 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.

In AML patients, greater than two fold increase in tipifarnib dosing can be tolerated on this dosing schedule with efficacy perhaps enhanced. Based on these promising results a monotherapy phase 2 or tipifarnib combination study in AML appears warranted.