Phase I and pharmacokinetic study of combined treatment with perifosine and radiation in patients with advanced solid tumours.
OBJECTIVE
Perifosine is an orally applicable, membrane-targeted alkylphosphocholine analogue with antitumour activity and radiosensitising properties in preclinical models. The purpose of this phase I study was to determine the feasibility and tolerability of concurrent daily perifosine and radiation in patients with advanced cancer.


METHODS
Starting dose of perifosine was 50 mg/day; dose escalation was in steps of 50mg. Daily administration commenced 2 days before radiotherapy and was continued throughout the radiation treatment. At least three patients were entered at each dose level; at the 150 mg/day level 10 patients were included. Pharmacokinetic sampling was performed weekly pre-dosing. Twenty-one patients were entered. Tumour types included NSCLC (n=17), prostate, oesophageal, colon and bladder cancer. Most patients (16/21) had received prior chemotherapy; none radiotherapy. Median number of daily perifosine administrations was 31 (range 24-53). Mean radiation dose (BED(10)) was 59.8 Gy (range 50.7-87.5 Gy in 13-28 fractions).


RESULTS
Major drug-related toxicities according to CTC criteria were nausea in 57%, fatigue in 48%, vomiting in 38%, diarrhoea in 38% and anorexia in 19%. No bone marrow toxicity was observed. DLT (nausea/vomiting) was encountered in two of five patients at the 200mg/day dose level. Dose-dependent steady-state plasma levels were reached after 1 week. Major radiotherapy-related acute toxicity consisted of dysphagia in 38% and pneumonitis in 29%.


CONCLUSIONS
Perifosine can be safely combined with fractionated radiotherapy. A dosage of 150 mg/day, to be started at least 1 week prior to radiotherapy, is recommended for phase II evaluation.
Vink
Stefan R
SR
Department of Radiation Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, The Netherlands.
Schellens
Jan H M
JH
Beijnen
Jos H
JH
Sindermann
Herbert
H
Engel
Jürgen
J
Dubbelman
Ria
R
Moppi
Gemi
G
Hillebrand
Michel J X
MJ
Bartelink
Harry
H
Verheij
Marcel
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy*; D010767:Phosphorylcholine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics
D000970:Antineoplastic Agents; D011838:Radiation-Sensitizing Agents; D010767:Phosphorylcholine; C105905:perifosine