Phase I and pharmacological study of daily oral administration of perifosine (D-21266) in patients with advanced solid tumours.
Alkylphosphocholines are a novel class of antitumour agents structurally related to ether lipids that interact with the cell membrane and influence intracellular growth signal transduction pathways. We performed a phase I trial with an analogue of miltefosine, perifosine (D-21266), which was expected to induce less gastrointestinal toxicity. Objectives of the trial were: to determine the maximum-tolerated dose (MTD) for daily administration, to identify the dose-limiting toxicity (DLT) of this schedule, to assess drug accumulation and to determine the relevant pharmacokinetic parameters. 22 patients with advanced solid tumours were treated at doses ranging from 50 to 350 mg/day for 3 weeks, followed by 1 week of rest. Toxicity consisted mainly of gastrointestinal side-effects: nausea was reported by 11 patients (52%, 10 patients Common Toxicity Criteria (CTC) grades 1-2 and 1 patient CTC grade 3), vomiting by 8 (38%, all CTC grades 1-2), and diarrhoea by 9 (43%, 8 patients CTC grades 1-2 and 1 patient CTC grade 3). The severity of these side effects appeared to increase with increasing doses. Another common side-effect was fatigue, occurring in 9 patients (43%). No haematology toxicity was observed. Dose-limiting toxicity (DLT) was not reached, but gastrointestinal complaints led to an early treatment discontinuation in an increasing number of patients at the higher dose levels. Therefore, MTD was established at 200 mg/day. The pharmacokinetic studies suggested dose proportionality.
Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. apmcr@slz.nl
M
M
Crul
H
H
Rosing
G J
GJ
de Klerk
R
R
Dubbelman
M
M
Traiser
S
S
Reichert
N G
NG
Knebel
J H M
JH
Schellens
J H
JH
Beijnen
W W
WW
ten Bokkel Huinink
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D008297:Male; D008452:Maximum Allowable Concentration; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D010767:Phosphorylcholine / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics
D000970:Antineoplastic Agents; D010767:Phosphorylcholine; C105905:perifosine