A two-part phase II study of cediranib in patients with advanced solid tumours: the effect of food on single-dose pharmacokinetics and an evaluation of safety, efficacy and imaging pharmacodynamics.
BACKGROUND
Cediranib (RECENTIN™) is an oral, highly potent VEGF inhibitor. This study evaluated the effect of food on the pharmacokinetics of cediranib and compared the administration of continual cediranib via two dosing strategies using this as a platform to investigate pharmacodynamic imaging biomarkers.


METHODS
Sixty patients were randomised to receive two single doses of cediranib in either fed/fasted or fasted/fed state (Part A). In continual dosage phase (Part B), patients were randomised to a fixed-dose or dose-escalation arm. Exploratory pharmacodynamic assessments were performed using DCE-MRI and CT enhancing fraction (EnF).


RESULTS
In part A, plasma AUC and C (max) of cediranib were lower in the presence of food by a mean of 24 and 33%, respectively (94% CI: AUC, 12-34% and C (max), 20-43%), indicating food reduces cediranib plasma exposure. In part B, cediranib 30 mg/day appeared to be the most sustainable for chronic dosing. Continuous cediranib therapy was associated with sustained antivascular effects up to 16 weeks, with significant reductions in DCE-MRI parameters and CT EnF.


CONCLUSIONS
It is recommended that cediranib be administered at least 1 h before or 2 h after food. Evidence of antitumour activity was observed, with significant sustained effects upon imaging vascular parameters.
Department of Medical Oncology, Christie Hospital NHS Trust, Withington, Manchester, UK. Claire.Mitchell@christie.nhs.uk
Claire L
CL
Mitchell
J P B
JP
O'Connor
C
C
Roberts
Y
Y
Watson
A
A
Jackson
S
S
Cheung
J
J
Evans
J
J
Spicer
A
A
Harris
C
C
Kelly
S
S
Rudman
M
M
Middleton
A
A
Fielding
J
J
Tessier
H
H
Young
G J M
GJ
Parker
G C
GC
Jayson
D000328:Adult; D000368:Aged; D019540:Area Under Curve; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects; D005215:Fasting / Q000378:metabolism; D005260:Female; D018565:Food-Drug Interactions; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011799:Quinazolines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D055815:Young Adult; D007211:Indoles
D011799:Quinazolines; C500926:cediranib; D007211:Indoles