A phase 1 trial dose-escalation study of tipifarnib on a week-on, week-off schedule in relapsed, refractory or high-risk myeloid leukemia.

Inhibition of farnesyltransferase (FT) activity has been associated with in vitro and in vivo anti-leukemia activity. We report the results of a phase 1 dose-escalation study of tipifarnib, an oral FT inhibitor, in patients with relapsed, refractory or newly diagnosed (if over age 70) acute myelogenous leukemia (AML), on a week-on, week-off schedule. Forty-four patients were enrolled, two patients were newly diagnosed, and the rest were relapsed or refractory to previous treatment, with a median age of 61 (range 33-79). The maximum tolerated dose was determined to be 1200 mg given orally twice daily (b.i.d.) on this schedule. Cycle 1 dose-limiting toxicities were hepatic and renal. There were three complete remissions seen, two at the 1200 mg b.i.d. dose and one at the 1000 mg b.i.d. dose, with minor responses seen at the 1400 mg b.i.d. dose level. Pharmacokinetic studies performed at doses of 1400 mg b.i.d. showed linear behavior with minimal accumulation between days 1-5. Tipifarnib administered on a week-on, week-off schedule shows activity at higher doses, and represents an option for future clinical trials in AML.

A comparison of the antiemetic efficacy of prochlorperazine and metoclopramide for the treatment of cisplatin-induced emesis: a prospective, randomized, double-blind study.

This study compared high-dose metoclopramide and prochlorperazine for their antiemetic activities in the treatment of patients with solid tumors receiving cisplatin-based cancer chemotherapy, in a prospective, double-blind fashion. Sixty patients were entered in the study, and 28 patients on each regimen were evaluable. For regimen 1, metoclopramide was given intravenously (IV) over 15 minutes at a dose of 2 mg/kg 30 minutes before, 30 minutes after, and three hours after treatment with cisplatin. In regimen 2, prochlorperazine was given IV 30 minutes before and three hours after the cisplatin; a placebo was administered at 30 minutes after cisplatin. There was no statistically significant difference between the two regimens in their antiemetic efficacies during the first three hours. For emesis that occurred from three to 24 hours after administration of cisplatin, prochlorperazine was marginally superior. The median number of emeses in the metoclopramide regimen was 2.5 (range, 0 to 10+) compared to 1.0 (range, 0 to 10+) in the prochlorperazine regimen. This is not a significant difference. The overall incidence of adverse reactions was greater in the metoclopramide regimen, with drowsiness being the most common toxicity for both antiemetic programs. Thus, IV high-dose metoclopramide and prochlorperazine are similar and effective in the management of cisplatin-induced emesis. IV prochlorperazine at 20-mg dosage is surprisingly effective.