A phase I and pharmacokinetic study of oral perifosine with different loading schedules in patients with refractory neoplasms

Abstract

Purpose: To determine the maximum tolerated dose (MTD) of perifosine (NSC 639966), an alkylphospholipid modulator of signal transduction, using different oral loading and maintenance regimens in an effort to avoid gastrointestinal toxicity while seeking maximal sustained plasma concentrations.

Methods: Thirty-one patients with advanced neoplasms were treated with monthly cycles of perifosine loading doses of 300, 600, 900, 1,200 and 1,500 mg (dose levels 1 through 5, respectively) on days 1-2 depending on the actual dose of the initial cycle. For subsequent cycles, perifosine loading doses were reduced to 100, 200, 300, 400 and 1,000 mg at the respective corresponding dose levels. Daily perifosine "maintenance" doses of 50, 100, 150, 200 and 250 mg for levels 1 through 5, respectively, commenced on days 2 or 3 and continued for a total of 21 days. No treatment was given for days 22-27. The pharmacokinetics of perifosine with these schedules was characterized.

Results: Dose-limiting diarrhea developed at or above dose level 4. The MTD and recommended phase II dose was dose level 3B, with a loading dose of 900 mg on day 1 divided into two doses of 450 mg administered 6 h apart and a maintenance dose of 150 mg on day 2 through 21. On subsequent cycles, the loading dose was reduced to 300 mg. Non-gastrointestinal toxicities included three episodes of gout or gout-like syndromes observed at doses above the MTD. The median peak plasma concentration of perifosine achieved at the MTD was approximately 8.3 µg/mL. Four patients had stable disease ranging from 167 to 735 days.

Conclusions: Perifosine given according to a loading and maintenance schedule can safely sustain concentrations of drug, approaching concentrations achieved in preclinical models with evidence of anti-tumor effect.

Fig. 1

Perifosine plasma concentration–time profile. The data were from 24 patients who received perifosine from dose level l to level 5 at cycle 1. Filled circle level l (n = 3), open circle level 2 (n = 3), filled square level 3 (n = 8), open square level 4 (n = 7), filled triang le level 5 (n = 3). Median concentrations are shown

Fig. 2

Perifosine plasma concentration versus doses. Perifosine concentrations at day 21 from dose level l to level 5 of cycle l were determined. Median values are represented by a line

Fig. 3

Perifosine plasma concentration at cycle l versus cycle 2. Data were perifosine concentrations at day 21 of each cycle from 10 patients. Filled cycle level l, open circle level 3, open triangle level 4,filled triangle level 5. Median values are represented by a line

Fig. 4

Simulated perifosine plasma concentration–time profile at dose level 3. A one-compartment linear model was applied. The solid line is predicted perifosine concentration–time profile in the presence of a loading dose. The dotted line is predicted perifosine concentration–time profile without a loading dose